Journal articles on the topic 'Oncogenic transformations'
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1
Paterno, G. D., L. L. Gillespie, M. S. Dixon, J. M. Slack, and J. K. Heath. "Mesoderm-inducing properties of INT-2 and kFGF: two oncogene-encoded growth factors related to FGF." Development 106, no. 1 (May 1, 1989): 79–83. http://dx.doi.org/10.1242/dev.106.1.79.
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Many theories of neoplasia suggest that oncogenic transformations result from aberrations in the control mechanisms which normally regulate growth and differentiation during embryonic development. It has recently become clear that many proto-oncogenes are differentially expressed during embryonic development and may thus be important embryonic regulatory molecules. We report here that the products of two transforming oncogenes int-2 and hst/ks (now called kfgf) can, with different potencies, induce mesoderm formation in isolated Xenopus laevis animal pole explants and stimulate DNA synthesis in mammalian fibroblasts. The results suggest that these proteins may function as mesoderm inducers in mammalian embryogenesis and that similar receptor/signalling pathways may be utilized for developmental and oncogenic processes. Finally, we have shown that the Xenopus assay system used in this study provides a powerful screen for protein factors that are active in development.
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Ito, Reina E., Chitose Oneyama, and Kazuhiro Aoki. "Oncogenic mutation or overexpression of oncogenic KRAS or BRAF is not sufficient to confer oncogene addiction." PLOS ONE 16, no. 4 (April 1, 2021): e0249388. http://dx.doi.org/10.1371/journal.pone.0249388.
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Oncogene addiction is a cellular property by which cancer cells become highly dependent on the expression of oncogenes for their survival. Oncogene addiction can be exploited to design molecularly targeted drugs that kill only cancer cells by inhibiting the specific oncogenes. Genes and cell lines exhibiting oncogene addiction, as well as the mechanisms by which cell death is induced when addicted oncogenes are suppressed, have been extensively studied. However, it is still not fully understood how oncogene addiction is acquired in cancer cells. Here, we take a synthetic biology approach to investigate whether oncogenic mutation or oncogene expression suffices to confer the property of oncogene addiction to cancer cells. We employed human mammary epithelium-derived MCF-10A cells expressing the oncogenic KRAS or BRAF. MCF-10A cells harboring an oncogenic mutation in a single-allele of KRAS or BRAF showed weak transformation activity, but no characteristics of oncogene addiction. MCF-10A cells overexpressing oncogenic KRAS demonstrated the transformation activity, but MCF-10A cells overexpressing oncogenic BRAF did not. Neither cell line exhibited any oncogene addiction properties. These results indicate that the introduction of oncogenic mutation or the overexpression of oncogenes is not sufficient for cells to acquire oncogene addiction, and that oncogene addiction is not associated with transformation activity.
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Calabrese, Fiorella, Federica Pezzuto, Francesca Lunardi, Francesco Fortarezza, Sofia-Eleni Tzorakoleftheraki, Maria Vittoria Resi, Mariaenrica Tiné, Giulia Pasello, and Paul Hofman. "Morphologic-Molecular Transformation of Oncogene Addicted Non-Small Cell Lung Cancer." International Journal of Molecular Sciences 23, no. 8 (April 9, 2022): 4164. http://dx.doi.org/10.3390/ijms23084164.
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Patients with non-small cell lung cancer, especially adenocarcinomas, harbour at least one oncogenic driver mutation that can potentially be a target for therapy. Treatments of these oncogene-addicted tumours, such as the use of tyrosine kinase inhibitors (TKIs) of mutated epidermal growth factor receptor, have dramatically improved the outcome of patients. However, some patients may acquire resistance to treatment early on after starting a targeted therapy. Transformations to other histotypes—small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and sarcomatoid carcinoma—have been increasingly recognised as important mechanisms of resistance and are increasingly becoming a topic of interest for all specialists involved in the diagnosis, management, and care of these patients. This article, after examining the most used TKI agents and their main biological activities, discusses histological and molecular transformations with an up-to-date review of all previous cases published in the field. Liquid biopsy and future research directions are also briefly discussed to offer the reader a complete and up-to-date overview of the topic.
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Clark, SS, Y. Liang, CK Reedstrom, and SQ Wu. "Nonrandom cytogenetic changes accompany malignant progression in clonal lines abelson virus-infected lymphocytes." Blood 84, no. 12 (December 15, 1994): 4301–9. http://dx.doi.org/10.1182/blood.v84.12.4301.bloodjournal84124301.
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Initially, lymphoid cells transformed by v-abl or BCR/ABL oncogenes are poorly oncogenic but progress to full transformation over time. Although expression of the oncogene is necessary to initiate and maintain transformation, other molecular mechanisms are thought to be required for full transformation. To determine whether tumor progression in ABL oncogene-transformed lymphoid cells has a genetic basis, we examined whether progression of the malignant phenotype of transformed clones correlates with particular cytogenetic abnormalities. A modified in vitro bone marrow transformation model was used to obtain clonal Abelson murine leukemia virus-transformed B lymphoid cells that were poorly oncogenic. Multiple subclones were then derived from each clone and maintained over a marrow-derived stromal cell line for several weeks. Over time, clonally related Abelson murine leukemia virus-transformed subclones progressed asynchronously to full transformation. The data show that tumor progression can occur in the absence of detectable cytogenetic changes but, more importantly, that certain cytogenetic abnormalities appear reproducibly in highly malignant subclones. Therefore, three independent subclones showed deletion in a common region of chromosome 13. Other highly malignant cells carried a common breakpoint in the X chromosome, and, finally, two subclones carried an additional chromosome 5. These results are consistent with the hypothesis that ABL oncogenes are sufficient for the initial transformation of cells but that additional genetic events can drive oncogenic progression. These observations further suggest that diverse genetic mechanisms may be able to drive tumor progression in cells transformed with ABL oncogenes.
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Alkharam, A. S., and D. E. Watt. "Risk Scaling Factors from Inactivation to Chromosome Aberrations, Mutations and Oncogenic Transformations in Mammalian Cells." Radiation Protection Dosimetry 70, no. 1 (April 1, 1997): 537–40. http://dx.doi.org/10.1093/oxfordjournals.rpd.a032012.
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Julien, Sylvie, Mirjana Radosavljevic, Nathalie Labouret, Sophie Camilleri-Broet, Frederic Davi, Martine Raphael, Thierry Martin, and Jean-Louis Pasquali. "AIDS Primary Central Nervous System Lymphoma: Molecular Analysis of the Expressed VH Genes and Possible Implications for Lymphomagenesis." Journal of Immunology 162, no. 3 (February 1, 1999): 1551–58. http://dx.doi.org/10.4049/jimmunol.162.3.1551.
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Abstract AIDS-associated primary central nervous system lymphomas are late events that have an extremely poor prognosis. Despite different hypotheses, the brain localization of these B cell lymphomas remains an enigma. To better define the cell origin of the lymphomas and the possible role of the B cell receptor (BCR) in the brain localization and/or in the oncogenic transformation, we analyzed the V region genes of the Ig heavy chain expressed by lymphoma cells in five randomly selected patients. After amplifying the rearranged VHDJH DNA by PCR, cloning, and sequencing of the amplified products, we observed that: 1) of the five lymphomas analyzed, four were clearly monoclonal; 2) there was no preferential use of one peculiar VH family or one peculiar segment of gene; 3) the mutation analysis showed that an Ag-driven process occurred in at least two cases, probably before the oncogenic event; and 4) there was no intraclonal variability, suggesting that the hypermutation mechanism is no longer efficient in these lymphoma B cells. Taken together, our results suggest that distinct Ags could be recognized by the BCR of the lymphoma cells in different patients and that, if the Ags are responsible for the brain localization of these B cells bearing mutated BCR, other factors must be involved in B cell transformations in primary central nervous system lymphoma.
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de Oliveira, Guilherme A. P., Elaine C. Petronilho, Murilo M. Pedrote, Mayra A. Marques, Tuane C. R. G. Vieira, Elio A. Cino, and Jerson L. Silva. "The Status of p53 Oligomeric and Aggregation States in Cancer." Biomolecules 10, no. 4 (April 4, 2020): 548. http://dx.doi.org/10.3390/biom10040548.
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Despite being referred to as the guardian of the genome, when impacted by mutations, p53 can lose its protective functions and become a renegade. The malignant transformation of p53 occurs on multiple levels, such as altered DNA binding properties, acquisition of novel cellular partners, or associating into different oligomeric states. The consequences of these transformations can be catastrophic. Ongoing studies have implicated different oligomeric p53 species as having a central role in cancer biology; however, the correlation between p53 oligomerization status and oncogenic activities in cancer progression remains an open conundrum. In this review, we summarize the roles of different p53 oligomeric states in cancer and discuss potential research directions for overcoming aberrant p53 function associated with them. We address how misfolding and prion-like amyloid aggregation of p53 seem to play a crucial role in cancer development. The misfolded and aggregated states of mutant p53 are prospective targets for the development of novel therapeutic strategies against tumoral diseases.
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Neitzel, Carina, Philipp Demuth, Simon Wittmann, and Jörg Fahrer. "Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities." Cancers 12, no. 7 (June 29, 2020): 1731. http://dx.doi.org/10.3390/cancers12071731.
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Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.
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Shrivastava, Richa, and Smrati Bhadauria. "Role of Growth Factor Signaling in Cancer." Defence Life Science Journal 1, no. 1 (June 1, 2016): 34. http://dx.doi.org/10.14429/dlsj.1.10059.
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<div class="page" title="Page 1"><div class="layoutArea"><div class="column"><div class="page" title="Page 1"><div class="layoutArea"><div class="column"><p><span>Growth factors may be defined as any group of protein that stimulate the growth of specific tissues and play an important role in promoting cellular differentiation and cellular division. Growth factors impart one of the important hallmark of cancer i.e sustaining proliferative signaling. They may act through paracrine, autocrine and endocrine signaling to effect growth and proliferation of cancer cells. They may act through various signaling cascades like MAPK, PI3K/AKT, JAK/STAT etc to activate their downstream mediates affecting various pathlogical and physiological functions. Abrupt signaling patterns of growth factors can induce oncogenic transformations. An enhanced understanding of these pathways can help targeting neoplastic transformation at an early stage. This review summarizes various mechanisms for targeted therapeutics against growth factor in cancer and their future prospective.</span></p></div></div></div></div></div></div><p> </p>
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Aggarwal, Vaishali, Hardeep Singh Tuli, Jagjit Kaur, Diwakar Aggarwal, Gaurav Parashar, Nidarshana Chaturvedi Parashar, Samruddhi Kulkarni, et al. "Garcinol Exhibits Anti-Neoplastic Effects by Targeting Diverse Oncogenic Factors in Tumor Cells." Biomedicines 8, no. 5 (April 30, 2020): 103. http://dx.doi.org/10.3390/biomedicines8050103.
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Garcinol, a polyisoprenylated benzophenone, is the medicinal component obtained from fruits and leaves of Garcinia indica (G. indica) and has traditionally been extensively used for its antioxidant and anti-inflammatory properties. In addition, it has been also been experimentally illustrated to elicit anti-cancer properties. Several in vitro and in vivo studies have illustrated the potential therapeutic efficiency of garcinol in management of different malignancies. It mainly acts as an inhibitor of cellular processes via regulation of transcription factors NF-κB and JAK/STAT3 in tumor cells and have been demonstrated to effectively inhibit growth of malignant cell population. Numerous studies have highlighted the anti-neoplastic potential of garcinol in different oncological transformations including colon cancer, breast cancer, prostate cancer, head and neck cancer, hepatocellular carcinoma, etc. However, use of garcinol is still in its pre-clinical stage and this is mainly attributed to the limitations of conclusive evaluation of pharmacological parameters. This necessitates evaluation of garcinol pharmacokinetics to precisely identify an appropriate dose and route of administration, tolerability, and potency under physiological conditions along with characterization of a therapeutic index. Hence, the research is presently ongoing in the dimension of exploring the precise metabolic mechanism of garcinol. Despite various lacunae, garcinol has presented with promising anti-cancer effects. Hence, this review is motivated by the constantly emerging and promising positive anti-cancerous effects of garcinol. This review is the first effort to summarize the mechanism of action of garcinol in modulation of anti-cancer effect via regulation of different cellular processes.
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Malumbres, Marcos, Ignacio Pérez De Castro, María I. Hernández, María Jiménez, Teresa Corral, and Angel Pellicer. "Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b." Molecular and Cellular Biology 20, no. 8 (April 15, 2000): 2915–25. http://dx.doi.org/10.1128/mcb.20.8.2915-2925.2000.
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ABSTRACT The cell cycle inhibitor p15 INK4b is frequently inactivated by homozygous deletion together with p16 INK4a and p19 ARF in some types of tumors. Although the tumor suppressor capability of p15 INK4b is still questioned, it has been found to be specifically inactivated by hypermethylation in hematopoietic malignancies in the absence of p16 INK4a alterations. Here we show that, in vitro, p15 INK4b is a strong inhibitor of cellular transformation by Ras. Surprisingly, p15 INK4b is induced in cultured cells by oncogenic Ras to an extent similar to that of p16 INK4a , and their expression is associated with premature G1 arrest and senescence. Ras-dependent induction of these two INK4 genes is mediated mainly by the Raf-Mek-Erk pathway. Studies with activated and dominant negative forms of Ras effectors indicate that the Raf-Mek-Erk pathway is essential for induction of both the p15 INK4b and p16 INK4a promoters, although other Ras effector pathways can collaborate, giving rise to a stronger response. Our results indicate that p15 INK4b , by itself, is able to stop cell transformation by Ras and other oncogenes such as Rgr (a new oncogene member of the Ral-GDS family, whose action is mediated through Ras). In fact, embryonic fibroblasts isolated from p15 INK4b knockout mice are susceptible to transformation by the Ras or Rgr oncogene whereas wild-type embryonic fibroblasts are not. Similarly, p15 INK4b -deficient mouse embryo fibroblasts are more sensitive than wild-type cells to transformation by a combination of the Rgr and E1A oncogenes. The cell cycle inhibitor p15 INK4b is therefore involved, at least in some cell types, in the tumor suppressor activity triggered after inappropriate oncogenic Ras activation in the cell.
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Ngalim, Siti Hawa, Astrid Magenau, Guillaume Le Saux, J. Justin Gooding, and Katharina Gaus. "How Do Cells Make Decisions: Engineering Micro- and Nanoenvironments for Cell Migration." Journal of Oncology 2010 (2010): 1–7. http://dx.doi.org/10.1155/2010/363106.
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Cell migration contributes to cancer metastasis and involves cell adhesion to the extracellular matrix (ECM), force generation through the cell's cytoskeletal, and finally cell detachment. Both adhesive cues from the ECM and soluble cues from neighbouring cells and tissue trigger intracellular signalling pathways that are essential for cell migration. While the machinery of many signalling pathways is relatively well understood, how hierarchies of different and conflicting signals are established is a new area of cellular cancer research. We examine the recent advances in microfabrication, microfluidics, and nanotechnology that can be utilized to engineer micro- and nanoscaled cellular environments. Controlling both adhesive and soluble cues for migration may allow us to decipher how cells become motile, choose the direction for migration, and how oncogenic transformations influences these decision-making processes.
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Nishizawa, Toshihiro, and Hidekazu Suzuki. "Gastric Carcinogenesis and Underlying Molecular Mechanisms:Helicobacter pyloriand Novel Targeted Therapy." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/794378.
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The oxygen-derived free radicals that are released from activated neutrophils are one of the cytotoxic factors ofHelicobacter pylori-induced gastric mucosal injury. Increased cytidine deaminase activity inH. pylori-infected gastric tissues promotes the accumulation of various mutations and might promote gastric carcinogenesis. Cytotoxin-associated gene A (CagA) is delivered into gastric epithelial cells via bacterial type IV secretion system, and it causes inflammation and activation of oncogenic pathways.H. pyloriinfection induces epigenetic transformations, such as aberrant promoter methylation in tumor-suppressor genes. Aberrant expression of microRNAs is also reportedly linked to gastric tumorogenesis. Moreover, recent advances in molecular targeting therapies provided a new interesting weapon to treat advanced gastric cancer through anti-human epidermal growth factor receptor 2 (HER-2) therapies. This updated review article highlights possible mechanisms of gastric carcinogenesis includingH. pylori-associated factors.
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Podstawski, Przemysław, Marcin Samiec, Maria Skrzyszowska, Tomasz Szmatoła, Ewelina Semik-Gurgul, and Katarzyna Ropka-Molik. "The Induced Expression of BPV E4 Gene in Equine Adult Dermal Fibroblast Cells as a Potential Model of Skin Sarcoid-like Neoplasia." International Journal of Molecular Sciences 23, no. 4 (February 10, 2022): 1970. http://dx.doi.org/10.3390/ijms23041970.
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The equine sarcoid is one of the most common neoplasias in the Equidae family. Despite the association of this tumor with the presence of bovine papillomavirus (BPV), the molecular mechanism of this lesion has not been fully understood. The transgenization of equine adult cutaneous fibroblast cells (ACFCs) was accomplished by nucleofection, followed by detection of molecular modifications using high-throughput NGS transcriptome sequencing. The results of the present study confirm that BPV-E4- and BPV-E1^E4-mediated nucleofection strategy significantly affected the transcriptomic alterations, leading to sarcoid-like neoplastic transformation of equine ACFCs. Furthermore, the results of the current investigation might contribute to the creation of in vitro biomedical models suitable for estimating the fates of molecular dedifferentiability and the epigenomic reprogrammability of BPV-E4 and BPV-E4^E1 transgenic equine ACFC-derived sarcoid-like cell nuclei in equine somatic cell-cloned embryos. Additionally, these in vitro models seem to be reliable for thoroughly recognizing molecular mechanisms that underlie not only oncogenic alterations in transcriptomic signatures, but also the etiopathogenesis of epidermal and dermal sarcoid-dependent neoplastic transformations in horses and other equids. For those reasons, the aforementioned transgenic models might be useful for devising clinical treatments in horses afflicted with sarcoid-related neoplasia of cutaneous and subcutaneous tissues.
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Hsieh, James J., Shugaku Takeda, David Y. Chen, Todd D. Westergard, Jill K. Fisher, Jeffrey A. Rubens, Satoru Sasagawa, Jason T. Kan, Stanley J. Korsmeyer, and Emily H. Cheng. "Proteolysis of MLL Family Proteins Is Essential for Taspase1−Orchestrated Cell Cycle Progression." Blood 108, no. 11 (November 16, 2006): 769. http://dx.doi.org/10.1182/blood.v108.11.769.769.
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Abstract Taspase1 was identified as the threonine endopeptidase that cleaves MLL for proper Hox gene expression in vitro. To investigate its functions in vivo, we generated Taspase1−/− mice. Taspase1 deficiency results in non−cleavage (nc) of MLL and MLL2 and homeotic transformations. Remarkably, our in vivo studies uncover an unexpected role of Taspase1 in cell cycle. Taspase1−/− animals are smaller in size. Taspase1−/− MEFs exhibit impaired proliferation and acute deletion of Taspase1 leads to a marked reduction of thymocytes. Taspase1 deficiency incurs down−regulation of Cyclin Es, As, and Bs and up−regulation of p16Ink4a. We show that MLL and MLL2 directly target E2Fs for Cyclin expression. The un−cleaved precursor MLL displays a reduced histone H3 methyl transferase activity in vitro. Accordingly, CHIP assays demonstrate a markedly decreased histone H3 K4 tri−methylation at Cyclin E1 and E2 genes in Taspase1−/− cells. Furthermore, MLLnc/nc;2nc/nc MEFs are also impaired in proliferation. Our data are consistent with a model in which precursor MLLs, activated by Taspase1, target to Cyclins through E2Fs to methylate histone H3 at K4, leading to activation. Lastly, Taspase1−/− cells are resistant to oncogenic transformation and Taspase1 is over−expressed in many cancer cell lines. Thus, Taspase1 may serve as a target for cancer therapeutics.
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Sankar, Savita, Jason M. Tanner, Russell Bell, Aashi Chaturvedi, R. Lor Randall, Mary C. Beckerle, and Stephen L. Lessnick. "A Novel Role for Keratin 17 in Coordinating Oncogenic Transformation and Cellular Adhesion in Ewing Sarcoma." Molecular and Cellular Biology 33, no. 22 (September 16, 2013): 4448–60. http://dx.doi.org/10.1128/mcb.00241-13.
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Oncogenic transformation in Ewing sarcoma is caused by EWS/FLI, an aberrant transcription factor fusion oncogene. Glioma-associated oncogene homolog 1 (GLI1) is a critical target gene activated by EWS/FLI, but the mechanism by which GLI1 contributes to the transformed phenotype of Ewing sarcoma was unknown. In this work, we identify keratin 17 (KRT17) as a direct downstream target gene upregulated by GLI1. We demonstrate that KRT17 regulates cellular adhesion by activating AKT/PKB (protein kinase B) signaling. In addition, KRT17 is necessary for oncogenic transformation in Ewing sarcoma and accounts for much of the GLI1-mediated transformation function but via a mechanism independent of AKT signaling. Taken together, our data reveal previously unknown molecular functions for a cytoplasmic intermediate filament protein, KRT17, in coordinating EWS/FLI- and GLI1-mediated oncogenic transformation and cellular adhesion in Ewing sarcoma.
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Farhana, Aisha, Avin Ee-Hwan Koh, Sangeetha Kothandan, Abdullah Alsrhani, Pooi Ling Mok, and Suresh Kumar Subbiah. "Treatment of HT29 Human Colorectal Cancer Cell Line with Nanocarrier-Encapsulated Camptothecin Reveals Histone Modifier Genes in the Wnt Signaling Pathway as Important Molecular Cues for Colon Cancer Targeting." International Journal of Molecular Sciences 22, no. 22 (November 13, 2021): 12286. http://dx.doi.org/10.3390/ijms222212286.
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Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction within the cell, which drives it towards oncogenic transformations. These epigenetic events augment cellular growth by potentially altering chromatin structures and influencing key gene expressions. Therapeutic mechanisms have been developed to combat this by taking advantage of the underlying oncogenic mechanisms through chemical modulation. Camptothecin (CPT) is an example of this type of drug. It is a selective topoisomerase I inhibitor that is effective against many cancers, such as colorectal cancer. Previously, we successfully formulated a magnetic nanocarrier-conjugated CPT with β-cyclodextrin and iron NPs (Fe3O4) cross-linked using EDTA (CPT-CEF). Compared to CPT alone, it boasts higher efficacy due to its selective targeting and increased solubility. In this study, we treated HT29 colon cancer cells with CPT-CEF and attempted to investigate the cytotoxic effects of the formulation through an epigenetic perspective. By using RNA-Seq, several differentially expressed genes were obtained (p < 0.05). Enrichr was then used for the over-representation analysis, and the genes were compared to the epigenetic roadmap and histone modification database. The results showed that the DEGs had a high correlation with epigenetic modifications involving histone H3 acetylation. Furthermore, a subset of these genes was shown to be associated with the Wnt/β-catenin signaling pathway, which is highly upregulated in a large number of cancer cells. These genes could be investigated as downstream therapeutic targets against the uncontrolled proliferation of cancer cells. Further interaction analysis of the identified genes with the key genes of the Wnt/β-catenin signaling pathway in colorectal cancer identified the direct interactors and a few transcription regulators. Further analysis in cBioPortal confirmed their genetic alterations and their distribution across patient samples. Thus, the findings of this study reveal that colorectal cancer could be reversed by treatment with the CPT-CEF nanoparticle-conjugated nanocarrier through an epigenetic mechanism.
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Giamougiannis, Panagiotis, Pierre L. Martin-Hirsch, and Francis L. Martin. "The evolving role of MUC16 (CA125) in the transformation of ovarian cells and the progression of neoplasia." Carcinogenesis 42, no. 3 (February 20, 2021): 327–43. http://dx.doi.org/10.1093/carcin/bgab010.
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Abstract MUC16 (the cancer antigen CA125) is the most commonly used serum biomarker in epithelial ovarian cancer, with increasing levels reflecting disease progression. It is a transmembrane glycoprotein with multiple isoforms, undergoing significant changes through the metastatic process. Aberrant glycosylation and cleavage with overexpression of a small membrane-bound fragment consist MUC16-related mechanisms that enhance malignant potential. Even MUC16 knockdown can induce an aggressive phenotype but can also increase susceptibility to chemotherapy. Variable MUC16 functions help ovarian cancer cells avoid immune cytotoxicity, survive inside ascites and form metastases. This review provides a comprehensive insight into MUC16 transformations and interactions, with description of activated oncogenic signalling pathways, and adds new elements on the role of its differential glycosylation. By following the journey of the molecule from pre-malignant states to advanced stages of disease it demonstrates its behaviour, in relation to the phenotypic shifts and progression of ovarian cancer. Additionally, it presents proposed differences of MUC16 structure in normal/benign conditions and epithelial ovarian malignancy.
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Borzillo, G. V., and C. J. Sherr. "Early pre-B-cell transformation induced by the v-fms oncogene in long-term mouse bone marrow cultures." Molecular and Cellular Biology 9, no. 9 (September 1989): 3973–81. http://dx.doi.org/10.1128/mcb.9.9.3973-3981.1989.
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Murine long-term bone marrow cultures that support B-lymphoid-cell development were infected with a helper-free retrovirus containing the v-fms oncogene. Infection of B-lymphoid cultures resulted in the rapid clonal outgrowth of early pre-B cells, which grew to high cell densities on stromal cell feeder layers, expressed v-fms-coded glycoproteins, and underwent immunoglobulin heavy-chain gene rearrangements. Late-passage cultures gave rise to factor-independent variants that proliferated in the absence of feeder layers, developed resistance to hydrocortisone, and became tumorigenic in syngeneic mice. The v-fms oncogene therefore recapitulates known effects of the v-abl and bcr-abl oncogenes on B-lineage cells. The ability of v-fms to induce transformation of early pre-B cells in vitro underscores the capacity of oncogenic mutants of the colony-stimulating factor-1 receptor to function outside the mononuclear phagocyte lineage.
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Borzillo, G. V., and C. J. Sherr. "Early pre-B-cell transformation induced by the v-fms oncogene in long-term mouse bone marrow cultures." Molecular and Cellular Biology 9, no. 9 (September 1989): 3973–81. http://dx.doi.org/10.1128/mcb.9.9.3973.
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Murine long-term bone marrow cultures that support B-lymphoid-cell development were infected with a helper-free retrovirus containing the v-fms oncogene. Infection of B-lymphoid cultures resulted in the rapid clonal outgrowth of early pre-B cells, which grew to high cell densities on stromal cell feeder layers, expressed v-fms-coded glycoproteins, and underwent immunoglobulin heavy-chain gene rearrangements. Late-passage cultures gave rise to factor-independent variants that proliferated in the absence of feeder layers, developed resistance to hydrocortisone, and became tumorigenic in syngeneic mice. The v-fms oncogene therefore recapitulates known effects of the v-abl and bcr-abl oncogenes on B-lineage cells. The ability of v-fms to induce transformation of early pre-B cells in vitro underscores the capacity of oncogenic mutants of the colony-stimulating factor-1 receptor to function outside the mononuclear phagocyte lineage.
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Liu, Yingting, Jeremy Purvis, Andrew Shih, Joshua Weinstein, Neeraj Agrawal, and Ravi Radhakrishnan. "A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations." Annals of Biomedical Engineering 35, no. 6 (February 2, 2007): 1012–25. http://dx.doi.org/10.1007/s10439-006-9251-0.
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Farhana, Aisha, Avin Ee-Hwan Koh, Jia Bei Tong, Abdullah Alsrhani, Suresh Kumar Subbiah, and Pooi Ling Mok. "Nanoparticle-Encapsulated Camptothecin: Epigenetic Modulation in DNA Repair Mechanisms in Colon Cancer Cells." Molecules 26, no. 17 (September 6, 2021): 5414. http://dx.doi.org/10.3390/molecules26175414.
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Molecular crosstalk between the cellular epigenome and genome converge as a synergistic driver of oncogenic transformations. Besides other pathways, epigenetic regulatory circuits exert their effect towards cancer progression through the induction of DNA repair deficiencies. We explored this mechanism using a camptothecin encapsulated in β-cyclodextrin–EDTA–Fe3O4 nanoparticles (CPT-CEF)-treated HT29 cells model. We previously demonstrated that CPT-CEF treatment of HT29 cells effectively induces apoptosis and cell cycle arrest, stalling cancer progression. A comparative transcriptome analysis of CPT-CEF-treated versus untreated HT29 cells indicated that genes controlling mismatch repair, base excision repair, and homologues recombination were downregulated in these cancer cells. Our study demonstrated that treatment with CPT-CEF alleviated this repression. We observed that CPT-CEF exerts its effect by possibly affecting the DNA repair mechanism through epigenetic modulation involving genes of HMGB1, APEX1, and POLE3. Hence, we propose that CPT-CEF could be a DNA repair modulator that harnesses the cell’s epigenomic plasticity to amend DNA repair deficiencies in cancer cells.
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Bitler, Benjamin G., Lauren S. Fink, Zhi Wei, Jeffrey R. Peterson, and Rugang Zhang. "A High-Content Screening Assay for Small-Molecule Modulators of Oncogene-Induced Senescence." Journal of Biomolecular Screening 18, no. 9 (June 3, 2013): 1054–61. http://dx.doi.org/10.1177/1087057113491827.
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Cellular senescence is a state of stable cell growth arrest. Activation of oncogenes such as RAS in mammalian cells typically triggers cellular senescence. Oncogene-induced senescence (OIS) is an important tumor suppression mechanism, and suppression of OIS contributes to cell transformation. Oncogenes trigger senescence through a multitude of incompletely understood downstream signaling events that frequently involve protein kinases. To identify target proteins required for RAS-induced senescence, we developed a small-molecule screen in primary human fibroblasts undergoing senescence induced by oncogenic RAS (H-RasG12V). Using a high-content imaging system to monitor two hallmarks of senescence, senescence-associated β-galactosidase activity expression and inhibition of proliferation, we screened a library of known small-molecule kinase inhibitors for those that suppressed OIS. Identified compounds were subsequently validated and confirmed using a third marker of senescence, senescence-associated heterochromatin foci. In summary, we have established a novel high-content screening platform that may be useful for elucidating signaling pathways mediating OIS by targeting critical pathway components.
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Harrington, M. A., F. Gonzales, and P. A. Jones. "Effect of cellular determination on oncogenic transformation by chemicals and oncogenes." Molecular and Cellular Biology 8, no. 10 (October 1988): 4322–27. http://dx.doi.org/10.1128/mcb.8.10.4322-4327.1988.
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Three developmentally determined myogenic cell lines derived from C3H 10T1/2 C18 (10T1/2) mouse embryo cells treated with 5-azacytidine were compared with the parental 10T1/2 line for their susceptibility to oncogenic transformation by 3-methylcholanthrene or the activated human c-Ha-ras oncogene. Neither the 10T1/2 cells nor the myogenic derivatives grew in soft agar or formed tumors in nude mice. In contrast to 10T1/2 cells, the three myogenic derivatives were not susceptible to transformation by 3-methylcholanthrene, so that cellular determination altered the response of 10T1/2 cells to chemical carcinogen. On the other hand, all cell types were transformed to a tumorigenic phenotype following transfection with the activated c-Ha-ras gene. The transfected myogenic cells expressed both the c-Ha-ras gene and the muscle determination gene MyoD1. In contrast to other reports, the presence of as many as six copies of the c-Ha-ras gene per genome did not prevent the formation of striated muscle cells which expressed immunologically detectable muscle-specific myosin. The expression of the c-Ha-ras gene does not therefore necessarily preclude the expression of the determination gene for myogenesis or prevent end-stage myogenic differentiation.
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Harrington, M. A., F. Gonzales, and P. A. Jones. "Effect of cellular determination on oncogenic transformation by chemicals and oncogenes." Molecular and Cellular Biology 8, no. 10 (October 1988): 4322–27. http://dx.doi.org/10.1128/mcb.8.10.4322.
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Three developmentally determined myogenic cell lines derived from C3H 10T1/2 C18 (10T1/2) mouse embryo cells treated with 5-azacytidine were compared with the parental 10T1/2 line for their susceptibility to oncogenic transformation by 3-methylcholanthrene or the activated human c-Ha-ras oncogene. Neither the 10T1/2 cells nor the myogenic derivatives grew in soft agar or formed tumors in nude mice. In contrast to 10T1/2 cells, the three myogenic derivatives were not susceptible to transformation by 3-methylcholanthrene, so that cellular determination altered the response of 10T1/2 cells to chemical carcinogen. On the other hand, all cell types were transformed to a tumorigenic phenotype following transfection with the activated c-Ha-ras gene. The transfected myogenic cells expressed both the c-Ha-ras gene and the muscle determination gene MyoD1. In contrast to other reports, the presence of as many as six copies of the c-Ha-ras gene per genome did not prevent the formation of striated muscle cells which expressed immunologically detectable muscle-specific myosin. The expression of the c-Ha-ras gene does not therefore necessarily preclude the expression of the determination gene for myogenesis or prevent end-stage myogenic differentiation.
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Xu, Shihao, Cody M. Spencer, and Joshua Munger. "Transformation with Oncogenic Ras and the Simian Virus 40 T Antigens Induces Caspase-Dependent Sensitivity to Fatty Acid Biosynthetic Inhibition." Journal of Virology 89, no. 12 (April 8, 2015): 6406–17. http://dx.doi.org/10.1128/jvi.03671-14.
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ABSTRACTOncogenesis is frequently accompanied by the activation of specific metabolic pathways. One such pathway is fatty acid biosynthesis, whose induction is observed upon transformation of a wide variety of cell types. Here, we explored how defined oncogenic alleles, specifically the simian virus 40 (SV40) T antigens and oncogenic Ras12V, affect fatty acid metabolism. Our results indicate that SV40/Ras12V-mediated transformation of fibroblasts induces fatty acid biosynthesis in the absence of significant changes in the concentration of fatty acid biosynthetic enzymes. This oncogene-induced activation of fatty acid biosynthesis was found to be mammalian target of rapamycin (mTOR) dependent, as it was attenuated by rapamycin treatment. Furthermore, SV40/Ras12V-mediated transformation induced sensitivity to treatment with fatty acid biosynthetic inhibitors. Pharmaceutical inhibition of acetyl-coenzyme A (CoA) carboxylase (ACC), a key fatty acid biosynthetic enzyme, induced caspase-dependent cell death in oncogene-transduced cells. In contrast, isogenic nontransformed cells were resistant to fatty acid biosynthetic inhibition. This oncogene-induced sensitivity to fatty acid biosynthetic inhibition was independent of the cells' growth rates and could be attenuated by supplementing the medium with unsaturated fatty acids. Both the activation of fatty acid biosynthesis and the sensitivity to fatty acid biosynthetic inhibition could be conveyed to nontransformed breast epithelial cells through transduction with oncogenic Ras12V. Similar to what was observed in the transformed fibroblasts, the Ras12V-induced sensitivity to fatty acid biosynthetic inhibition was independent of the proliferative status and could be attenuated by supplementing the medium with unsaturated fatty acids. Combined, our results indicate that specific oncogenic alleles can directly confer sensitivity to inhibitors of fatty acid biosynthesis.IMPORTANCEViral oncoproteins and cellular mutations drive the transformation of normal cells to the cancerous state. These oncogenic alterations induce metabolic changes and dependencies that can be targeted to kill cancerous cells. Here, we find that the cellular transformation resulting from combined expression of the SV40 early region with an oncogenic Ras allele is sufficient to induce cellular susceptibility to fatty acid biosynthetic inhibition. Inhibition of fatty acid biosynthesis in these cells resulted in programmed cell death, which could be rescued by supplementing the medium with nonsaturated fatty acids. Similar results were observed with the expression of oncogenic Ras in nontransformed breast epithelial cells. Combined, our results suggest that specific oncogenic alleles induce metabolic dependencies that can be exploited to selectively kill cancerous cells.
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Xu, Mai, Qing Yu, Ramesh Subrahmanyam, Michael J. Difilippantonio, Thomas Ried, and Jyoti Misra Sen. "β-Catenin Expression Results in p53-Independent DNA Damage and Oncogene-Induced Senescence in Prelymphomagenic Thymocytes In Vivo." Molecular and Cellular Biology 28, no. 5 (December 26, 2007): 1713–23. http://dx.doi.org/10.1128/mcb.01360-07.
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ABSTRACT The expression of β-catenin, a potent oncogene, is causally linked to tumorigenesis. Therefore, it was surprising that the transgenic expression of oncogenic β-catenin in thymocytes resulted in thymic involution instead of lymphomagenesis. In this report, we demonstrate that this is because the expression of oncogenic β-catenin induces DNA damage, growth arrest, oncogene-induced senescence (OIS), and apoptosis of immature thymocytes. In p53-deficient mice, the expression of oncogenic β-catenin still results in DNA damage and OIS, but the thymocytes survive and eventually progress to thymic lymphoma. β-Catenin-induced thymic lymphomas are distinct from lymphomas that arise in p53−/− mice. They are CD4− CD8−, while p53-dependent lymphomas are largely CD4+ CD8+, and they develop at an earlier age and in the absence of c-Myc expression or Notch1 signaling. Thus, we report that oncogenic β-catenin-induced, p53-independent growth arrest and OIS and p53-dependent apoptosis protect developing thymocytes from transformation by oncogenic β-catenin.
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Maeda, Takahiro, Robin Hobbs, Taha Merghoub, Ilhem Guernah, Arthur Zelent, Julie Teruya-Feldstein, and Pier Paolo Pandolfi. "POKEMON Is a Proto-Oncogene Which Plays a Key Role in Lymphomagenesis." Blood 104, no. 11 (November 16, 2004): 3489. http://dx.doi.org/10.1182/blood.v104.11.3489.3489.
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Abstract POKEMON (for POK, Erythroid, Myeloid ONtogenic factor, also known as LRF) was originally isolated as a homologue of PLZF (Promyelocytic Leukemia Zinc Finger) which can physically interact with the BCL6 (B Cell Lymphoma 6) proto-oncogene. Analysis of Pokemon−/− mice demonstrates that this transcriptional repressor plays a key developmental role whose function is required for cellular differentiation in multiple tissues such as skin, adipose tissue and hematopoietic lineage cells. Taking advantage of Pokemon−/− MEFs (Mouse Embryonic Fibroblasts), we found that Pokemon is indispensable for cellular transformation mediated by oncogenes (such as BCL6, E1A, H-RasV12, c-Myc, or T-Ag) and Pokemon overexpression overcomes oncogene induced premature senescence and apoptosis leading to oncogenic transformation by repressing p19ARF tumor suppressor. Furthermore, Pokemon−/− MEFs showed a premature senescence phenotype in early passage which was rescued by inactivation of p19ARF. To explore the oncogenic role of Pokemon in vivo, we generated Lck/Eμ Pokemon transgenic mice in which Pokemon is over expressed in T and B lineage cells under the control of Lck/Eμ promoter/enhancer. Strikingly, about 50% of the mice developed T lymphoblastic lymphoma (CD4+, CD8+, CD44 + and TdT+) after a latent period of 2 to 4 months. As Pokemon expression proved essential for cellular transformation and is oncogenic when overexpressed in vivo, we analyzed the levels of POKEMON expression in human cancers, performing Tissue Microarray Analysis (TMA). We first analyzed human B-cell lymphomas as POKEMON is normally co-expressed with BCL6 in the B-cell within the germinal center, and may therefore cooperate with BCL6 in lymphomagenesis. We analyzed and scored a total of 123 cases of diffuse large B-cell lymphoma (DLBCL) and 290 cases of follicular lymphoma (FL) for POKEMON protein expression levels. POKEMON was highly expressed in 25–35% and moderately expressed in 40–50% of both DLBCL and FL clinical samples. Strikingly, as previously shown for BCL6, POKEMON positivity predicted a better prognosis of overall survival in DLBCL. Interestingly, the vast majority (approximately 80%) of BCL6 positive DLBCLs and FLs were found to be POKEMON positive. By contrast, not all the POKEMON positive lymphomas expressed BCL6. Importantly, coexpression of POKEMON and BCL6 in DLBCL predicted an even better clinical outcome, identifying a clinically distinct DLBCL subtype.
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Land, H., A. C. Chen, J. P. Morgenstern, L. F. Parada, and R. A. Weinberg. "Behavior of myc and ras oncogenes in transformation of rat embryo fibroblasts." Molecular and Cellular Biology 6, no. 6 (June 1986): 1917–25. http://dx.doi.org/10.1128/mcb.6.6.1917-1925.1986.
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The requirements for transformation of rat embryo fibroblasts (REFs) by transfected ras and myc oncogenes were explored. Under conditions of dense monolayer culture, neither oncogene was able to transform REFs on its own. However, the introduction of a ras oncogene together with a selectable neomycin resistance marker into REFs allowed killing of the normal nontransfected cells and the outgrowth of colonies of ras transformants, 10% of which survived crisis and became tumorigenic. These cells expressed greater than 10-fold-higher levels of ras p21 than tumorigenic cells cotransfected with ras and myc oncogenes. The myc oncogene similarly was unable to induce tumorigenic conversion of REFs unless especially refractile colonies of oncogene-bearing cells, produced by use of a cotransfected selectable marker, were picked and subcultured. Tumorigenic conversion of REFs by single transfected oncogenes appears to require special culture conditions and high levels of gene expression.
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Land, H., A. C. Chen, J. P. Morgenstern, L. F. Parada, and R. A. Weinberg. "Behavior of myc and ras oncogenes in transformation of rat embryo fibroblasts." Molecular and Cellular Biology 6, no. 6 (June 1986): 1917–25. http://dx.doi.org/10.1128/mcb.6.6.1917.
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The requirements for transformation of rat embryo fibroblasts (REFs) by transfected ras and myc oncogenes were explored. Under conditions of dense monolayer culture, neither oncogene was able to transform REFs on its own. However, the introduction of a ras oncogene together with a selectable neomycin resistance marker into REFs allowed killing of the normal nontransfected cells and the outgrowth of colonies of ras transformants, 10% of which survived crisis and became tumorigenic. These cells expressed greater than 10-fold-higher levels of ras p21 than tumorigenic cells cotransfected with ras and myc oncogenes. The myc oncogene similarly was unable to induce tumorigenic conversion of REFs unless especially refractile colonies of oncogene-bearing cells, produced by use of a cotransfected selectable marker, were picked and subcultured. Tumorigenic conversion of REFs by single transfected oncogenes appears to require special culture conditions and high levels of gene expression.
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Ly, Tony, Aki Endo, Alejandro Brenes, Marek Gierlinski, Vackar Afzal, Andrea Pawellek, and Angus I. Lamond. "Proteome-wide analysis of protein abundance and turnover remodelling during oncogenic transformation of human breast epithelial cells." Wellcome Open Research 3 (May 2, 2018): 51. http://dx.doi.org/10.12688/wellcomeopenres.14392.1.
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Background: Viral oncogenes and mutated proto-oncogenes are potent drivers of cancer malignancy. Downstream of the oncogenic trigger are alterations in protein properties that give rise to cellular transformation and the acquisition of malignant cellular phenotypes. Developments in mass spectrometry enable large-scale, multidimensional characterisation of proteomes. Such techniques could provide an unprecedented, unbiased view of how oncogene activation remodels a human cell proteome. Methods: Using quantitative MS-based proteomics and cellular assays, we analysed how transformation induced by activating v-Src kinase remodels the proteome and cellular phenotypes of breast epithelial (MCF10A) cells. SILAC MS was used to comprehensively characterise the MCF10A proteome and to measure v-Src-induced changes in protein abundance across seven time-points (1-72 hrs). We used pulse-SILAC MS (Boisvert et al., 2012), to compare protein synthesis and turnover in control and transformed cells. Follow-on experiments employed a combination of cellular and functional assays to characterise the roles of selected Src-responsive proteins. Results: Src-induced transformation changed the expression and/or turnover levels of ~3% of proteins, affecting ~1.5% of the total protein molecules in the cell. Transformation increased the average rate of proteome turnover and disrupted protein homeostasis. We identify distinct classes of protein kinetics in response to Src activation. We demonstrate that members of the polycomb repressive complex 1 (PRC1) are important regulators of invasion and migration in MCF10A cells. Many Src-regulated proteins are present in low abundance and some are regulated post-transcriptionally. The signature of Src-responsive proteins is highly predictive of poor patient survival across multiple cancer types. Open access to search and interactively explore all these proteomic data is provided via the EPD database (www.peptracker.com/epd). Conclusions: We present the first comprehensive analysis measuring how protein expression and protein turnover is affected by cell transformation, providing a detailed picture at the protein level of the consequences of activation of an oncogene.
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Sasaki, Rumi, Mako Narisawa-Saito, Takashi Yugawa, Masatoshi Fujita, Hironori Tashiro, Hidetaka Katabuchi, and Tohru Kiyono. "Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes." Carcinogenesis 30, no. 3 (January 6, 2009): 423–31. http://dx.doi.org/10.1093/carcin/bgp007.
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Chan, Lai N., Christian Hurtz, Huimin Geng, Franziska Auer, Zhengshan Chen, Gang Xiao, Jae-Woong Lee, Kadriye Nehir Cosgun, B. Hilda Ye, and Markus Muschen. "Ras-Driven B-Cell Transformation Targets Developmental Rewiring of Cytokine to Pre-B Cell Receptor Signaling." Blood 132, Supplement 1 (November 29, 2018): 1336. http://dx.doi.org/10.1182/blood-2018-99-115514.
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Abstract Ras-pathway lesions are oncogenic drivers in ~45% of B-cell acute lymphoblastic leukemia (B-ALL) cases. Activating mutations of NRAS and KRAS are oncogenic drivers in B-ALL while the BRAFV600E mutation occurs in almost all cases of B-cell hairy cell leukemia. Less frequent lesions resulting in increased ERK-signaling in B-cell malignancies include activating mutations of RAF1, MAP2K1 and the PTPN11 phosphatase as well as deleterious mutations of the Ras-GTPase activator NF1. Interestingly, increased immunoglobulin light chain gene expression was observed in B-ALL cases with RAS-pathway lesions (COG P9906), reflecting engagement of pre-B cell receptor (pre-BCR) downstream signaling. Here we tested the hypothesis that oncogenic RAS-signaling in B-ALL mimics pre-BCR-induced developmental rewiring of signal transduction at the pro-B to pre-B cell transition and identified PTPN6 and BCL6 as therapeutic targets in RAS-driven B-ALL. During early B-cell development, pro-B cells transition from cytokine- to pre-B cell receptor (pre-BCR)-dependent survival and proliferation signals. Inducible activation of immunoglobulin (Ig) µ heavy chain (µHC) expression induced developmental progression and surface expression of Ig κ light chains. Notably, inducible activation of oncogenic NRASG12D had the same effect and resulted in increased surface expression of Ig κ light chains. Furthermore, studying genetic models for this transition revealed that both pre-BCR signaling and RAS-oncogenes suppressed cytokine receptor/STAT5-signaling and induced massive de novo expression of the proto-oncogene and transcriptional repressor BCL6. Our genetic studies revealed that the SH2-domain containing protein tyrosine phosphatase PTPN6 was activated by oncogenic RAS-signaling and essential for the switch from STAT5 to BCL6-activation. Given that oncogenic RAS activated PTPN6, we tested the role of PTPN6 in RAS-driven leukemogenesis. To this end, ablation of Ptpn6 in NRASG12D-driven B-ALL resulted in depletion of cells from cell culture in competitive-growth assays and reduced the number of colonies formed in semi-solid methylcellulose. Collectively, these findings suggest that PTPN6 represents a potential therapeutic intervention point in RAS-driven B-ALL. In addition to PTPN6, we investigated the role of BCL6 in RAS-driven B-ALL. Aberrant activation of oncogenic RAS results in oncogene-induced senescence (OIS) characterized by induction of ARF/p53 and irreversible cell cycle arrest in the G1 phase. For oncogenic Ras-signaling, BCL6 was required to oppose ERK-mediated activation of p21, p27 and p53 checkpoint molecules in B-ALL. Here we tested the hypothesis that BCL6 bypasses the RAS-mediated OIS program to facilitate transformation. To this end, increases in number of colonies formed in semi-solid methylcellulose were observed upon inducible activation of Bcl6 in NRASG12D B-ALL cells. Furthermore, loss of Bcl6 function in NRASG12D B-ALL cells resulted in depletion of cells from cell culture in competitive growth assays and reduced colony forming ability. Importantly, expression of NRASG12D in Bcl6+/+ pre-B cells resulted in transformation and fatal leukemia in transplant recipient mice. In striking contrast, Bcl6-/- pre-B cells transduced with NRASG12D failed to initiate fatal disease in vivo. Furthermore, pharmacological inhibition of BCL6 restored sensitivity to chemotherapy in patient-derived KRASG12V B-ALL cells. In conclusion, we identified oncogenic RAS-signaling as functional mimics of pre-BCR signaling. Oncogenic RAS induced expression of BCL6 at the expense of cytokine receptor/STAT5-signaling. Our genetic studies identified PTPN6 as a critical effector molecule of the switch from cytokine receptor to pre-BCR signaling. Importantly, we identified PTPN6 and BCL6 as potential therapeutic intervention points in RAS-driven B-ALL. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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García-Silva, Susana, and Ana Aranda. "The Thyroid Hormone Receptor Is a Suppressor of ras-Mediated Transcription, Proliferation, and Transformation." Molecular and Cellular Biology 24, no. 17 (September 1, 2004): 7514–23. http://dx.doi.org/10.1128/mcb.24.17.7514-7523.2004.
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ABSTRACT The thyroid hormone triiodothyronine (T3) has a profound effect on growth, differentiation, and metabolism in higher organisms. Here we demonstrate that T3 inhibits ras-induced proliferation in neuroblastoma cells and blocks induction of cyclin D1 expression by the oncogene. The hormone, at physiological concentrations, strongly antagonizes the transcriptional response mediated by the Ras/mitogen-activated protein kinase/ribosomal-S6 subunit kinase (Rsk) signaling pathway in cells expressing thyroid hormone receptors (TRs). T3 blocks the response to the oncogenic forms of the three ras isoforms (H-, K-, and N-ras) and both TRα and TRβ can mediate this action. The main target for induction of cyclin D1 transcription by oncogenic ras in neuroblastoma cells is a cyclic AMP response element (CRE) located in proximal promoter sequences, and T3 represses the transcriptional activity of b-Zip transcription factors such as CREB (CRE-binding protein) or ATF-2 (activation transcription factor 2) that are direct targets of Rsk2 and bind to this sequence. The hormone also blocks fibroblast transformation by oncogenic ras when TR is expressed. Furthermore, TRs act as suppressors of tumor formation by the oncogene in vivo in nude mice. The TRβ isoform has stronger antitransforming properties than the α isoform and can inhibit tumorigenesis even in hypothyroid mice. These results show the existence of a previously unrecognized transcriptional cross talk between the TRs and the ras oncogene which influences relevant processes such as cell proliferation, transformation, or tumorigenesis.
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De, Pradip, Brett James Rozeboom, Jennifer Carlson Aske, and Nandini Dey. "Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors." Cancers 12, no. 6 (June 11, 2020): 1541. http://dx.doi.org/10.3390/cancers12061541.
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Acting as molecular switches, all three members of the Guanosine triphosphate (GTP)-ase-family, Ras-related C3 botulinum toxin substrate (RAC), Rho, and Cdc42 contribute to various processes of oncogenic transformations in several solid tumors. We have reviewed the distribution of patterns regarding the frequency of Ras-related C3 botulinum toxin substrate 1 (RAC1)-alteration(s) and their modes of actions in various cancers. The RAC1 hyperactivation/copy-number gain is one of the frequently observed features in various solid tumors. We argued that RAC1 plays a critical role in the progression of tumors and the development of resistance to various therapeutic modalities applied in the clinic. With this perspective, here we interrogated multiple functions of RAC1 in solid tumors pertaining to the progression of tumors and the development of resistance with a special emphasis on different tumor cell phenotypes, including the inhibition of apoptosis and increase in the proliferation, epithelial-to-mesenchymal transition (EMT), stemness, pro-angiogenic, and metastatic phenotypes. Our review focuses on the role of RAC1 in adult solid-tumors and summarizes the contextual mechanisms of RAC1 involvement in the development of resistance to cancer therapies.
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Ntziachristos, Panagiotis, Kelly Arcipowski, Carlos Alberto Martinez, Yixing Zhu, Andrew G. Volk, Suresh Kumar, Paul M. Thomas, et al. "Therapeutic Targeting of the Histone Ubiquitination-Methylation Axis in T Cell Leukemia." Blood 128, no. 22 (December 2, 2016): 1532. http://dx.doi.org/10.1182/blood.v128.22.1532.1532.
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Abstract Acute lymphoblastic leukemia (ALL) is a highly aggressive blood cancer affecting children and adults. Certain high-risk disease subsets have poor outcomes and often debilitating therapy-related toxicities stemming from direct inhibition of the oncogenes. We hypothesize that the process of oncogenic transformation is driven by aberrant activity of oncogene-associated chromatin modifying partners. These changes create a chromatin environment unique to the malignant state and, therefore, disruption of critical oncogenic chromatin signatures would not likely affect healthy tissues. We have generated strong evidence for the intertwined roles between the NOTCH1 oncogenic pathway and deubiquitinase enzymes in T cell leukemia, members of the ubiquitin-specific proteases (USP) family in particular. Members of the USP family physically interact with NOTCH1 and the lysine 27 on histone H3 (H3K27) demethylase JMJD3 and this methylation-ubiquitination biology-related axis coordinates regulation of transcriptional initiation and elongation, vital for the survival of leukemia cells. Interestingly transcription of USP genes is positively controlled by NOTCH1 creating a feedback loop in leukemia. We have further characterized this oncogenic axis using a combination of small molecule inhibitors and genetic engineering of USPs in ALL cell lines, primary patient samples and primagraft models of disease. We are able to show that a) USP activity is important for certain oncogenic pathways (such as NOTCH1) in leukemia; b) Oncogenes and USP enzymes co-bind certain areas in the leukemia genome; c) Ubiquitination of histone H2B acts in a combinatorial fashion with H3K27me, is a major epigenetic change affected by the USP activity in leukemia and controls d) transcriptional elongation. Finally we demonstrate that f) chemical inhibition or down-regulation of USPs affect leukemia growth in vitro and in vivo. Ongoing and future studies include manipulation of USP levels in mouse models of leukemia as well as combinatorial use of USP inhibitors with chemotherapeutic regiments in vitro using matched diagnosis-relapsed primary samples and in xenograft studies. Information gained from these studies will lend rationale towards the use of small molecule inhibitors against USP proteins in clinical trials for the treatment of aggressive and relapsed ALL. Disclosures Kumar: Progenra Inc.: Employment. Wang:Progenra Inc.: Employment. Wu:Progenra Inc.: Employment.
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Alghisi, Elisa, Michele Malagola, Cristina Santoriello, Cristina Skert, Carla Filì, Cesare Bergonzi, Annalisa Peli, et al. "Establishing a New Zebrafish Model to Study Malignant Transformation in Myeloproliferative Disorders." Blood 118, no. 21 (November 18, 2011): 4711. http://dx.doi.org/10.1182/blood.v118.21.4711.4711.
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Abstract Abstract 4711 Background: Myeloproliferative diseases (MPDs) are a group of hematological malignancies characterized by the abnormal increase of different blood cells in peripheral blood and in other hematological organs. The molecular pathways involved in disease pathogenesis and progression as well as in drug sensitivity and resistance are not fully elucidated yet. Given the physiological similarity to mammals, the zebrafish (ZF) could accelerate the study of the molecular basis of these diseases. In the last decade several human leukaemia associated oncogenes have been transiently over-expressed in ZF embryos in order to perturb the myelo-erythroid compartment, with the aim to create experimental models to discover new molecular pathways that can became potential targets for new chemical compounds. Methodogy: We took advantage of the binary Gal4/UAS system to express oncogenic human HRAS in the ZF hematopoietic compartment. We used the tg(MAZe) driver line, a specific transgenic line that allows random mosaic expression of Gal4-VP16 after heat shock(hs) treatment(1). This driver line was mated with a tg(UAS:eGFP-HRASV12)(2) responder line in order to mimic somatic events leading to human oncogene expression. Results: Surprisingly a single heat shock at 30hpf, (referred here as HRASV12hs) induces human HRASV12 expression in hematopoietic progenitors as judged by the expansion of the hematopoietic tissue. Histological analysis showed an increased number of monocytes/macrophages. Blood smear of HRASV12hs larvae showed the expansion of blasts and myeloid precursors. Quantitative analysis of gene expression highlights a remarkable increase of myelo-erythroid restricted genes associated with a slight increase of staminality markers (pu1, mpx, lmo2, mpl, CD41 and c-myb). Moreover fish raised to adulthood developed hyper-plastic kidney marrow, the site of definitive haematopoiesis, the equivalent of mammalian bone marrow. Conclusions and Future Perspectives: The combination of hyper-proliferation of blood cells associated with the expansion of the hematopoietic compartment that we found in this model reproduces the pathological features of human myeloproliferative disorders. This study shows that it is possible to drive the expression of leukemia associated oncogenes to the hematopoietic compartment in developing ZF thus reproducing some of the features of human blood malignancies in an in vivo model. Our Group is now testing different driver lines in order to induce oncogene expression in earliest hematopoietic progenitors and is focusing on different responder lines expressing human oncogenes involved in hematopoietic malignancies. Disclosures: No relevant conflicts of interest to declare.
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Guo, Beichu, and Jinyu Zhang. "Senescence associated inflammasome (SAI) activation promotes cancer progression (TUM4P.909)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 138.10. http://dx.doi.org/10.4049/jimmunol.192.supp.138.10.
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Abstract Oncogene-induced senescence functions as a barrier against cell transformation and tumorigenesis. Paradoxically, recent studies indicate that senescence also promotes tumor progression through secretion of inflammatory molecules or senescence-associated secretory phenotype (SASP). However, the signaling pathways leading to SASP and the interaction between senescent cells and innate immune cells are poorly understood. Utilizing human and murine breast cancer cells, as well as breast cancer mouse models, this study demonstrates that senescence-associated inflammasome (SAI) generate a positive feedback loop to propagate inflammation through interaction with innate immune cells, contributing to the tumor development. Our data show that cellular senescence induced by oncogenes, such as K-Ras12V and Her2/ERBB2, led to inflammasome activation and IL-1beta production in both murine and human breast cancer cells. Notably, we found that blocking inflammasome activity could suppress both IL-1beta production and oncogene-induced senescence in breast cancer cells. Our results further show that the crosstalk between senescent cells and innate immune cells promoted inflammation and breast cancer progression. Together, our findings demonstrate a critical role for the senescence-associated inflammasome in oncogenic inflammation and tumor development.
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Mali, Raghuveer Singh, Peilin Ma, Li-Fan Zeng, Holly Martin, Baskar Ramdas, Yantao He, Emily Sims, et al. "Role of SHP2 phosphatase in KIT-induced transformation: identification of SHP2 as a druggable target in diseases involving oncogenic KIT." Blood 120, no. 13 (September 27, 2012): 2669–78. http://dx.doi.org/10.1182/blood-2011-08-375873.
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Abstract Intracellular mechanism(s) that contribute to promiscuous signaling via oncogenic KIT in systemic mastocytosis and acute myelogenous leukemia are poorly understood. We show that SHP2 phosphatase is essential for oncogenic KIT-induced growth and survival in vitro and myeloproliferative disease (MPD) in vivo. Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85α, SHP2, and Gab2. Importantly, a single tyrosine at position 719 in oncogenic KIT is sufficient to develop MPD by recruiting p85α, SHP2, and Gab2 complex to oncogenic KIT. Our results demonstrate that SHP2 phosphatase is a druggable target that cooperates with lipid kinases in inducing MPD.
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Kannan, Perry, and Michael A. Tainsky. "Coactivator PC4 Mediates AP-2 Transcriptional Activity and Suppresses ras-Induced Transformation Dependent on AP-2 Transcriptional Interference." Molecular and Cellular Biology 19, no. 1 (January 1, 1999): 899–908. http://dx.doi.org/10.1128/mcb.19.1.899.
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ABSTRACT ras oncogene-transformed PA-1 human teratocarcinoma cells have abundant AP-2 mRNA but, paradoxically, little AP-2 transcriptional activity. We have previously shown that overexpression of AP-2 in nontumorigenic variants of PA-1 cells results in inhibition of AP-2 activity and induction of tumorigenicity similar to that caused by ras transformation of PA-1 cells. Evidence indicated the existence of a novel mechanism of inhibition of AP-2 activity involving sequestering of transcriptional coactivators. In this study, we found that PC4 is a positive coactivator of AP-2 and can restore AP-2 activity in ras-transformed PA-1 cells. Relative to vector-transfected ras cell lines,ras cell lines stably transfected with and expressing the PC4 cDNA have a diminished growth rate and exhibit a loss of anchorage-independent growth, and they are unable to induce the formation of tumors in nude mice. These data suggest that a transcriptional coactivator, like a tumor suppressor, can have a growth-suppressive effect on cells. Our experiments are the first to show that ras oncogenes and oncogenic transcription factors can induce transformation through effects on the transcription machinery rather than through specific programs of gene expression.
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Bose, Indrani. "Tipping the Balance: A Criticality Perspective." Entropy 24, no. 3 (March 14, 2022): 405. http://dx.doi.org/10.3390/e24030405.
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Cell populations are often characterised by phenotypic heterogeneity in the form of two distinct subpopulations. We consider a model of tumour cells consisting of two subpopulations: non-cancer promoting (NCP) and cancer-promoting (CP). Under steady state conditions, the model has similarities with a well-known model of population genetics which exhibits a purely noise-induced transition from unimodality to bimodality at a critical value of the noise intensity σ2. The noise is associated with the parameter λ representing the system-environment coupling. In the case of the tumour model, λ has a natural interpretation in terms of the tissue microenvironment which has considerable influence on the phenotypic composition of the tumour. Oncogenic transformations give rise to considerable fluctuations in the parameter. We compute the λ−σ2 phase diagram in a stochastic setting, drawing analogies between bifurcations and phase transitions. In the region of bimodality, a transition from a state of balance to a state of dominance, in terms of the competing subpopulations, occurs at λ = 0. Away from this point, the NCP (CP) subpopulation becomes dominant as λ changes towards positive (negative) values. The variance of the steady state probability density function as well as two entropic measures provide characteristic signatures at the transition point.
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Ladenson, P. W. "Optimal laboratory testing for diagnosis and monitoring of thyroid nodules, goiter, and thyroid cancer." Clinical Chemistry 42, no. 1 (January 1, 1996): 183–87. http://dx.doi.org/10.1093/clinchem/42.1.183.
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Abstract Optimal use of laboratory tests to diagnose and monitor patients with goiter, thyroid nodules, or thyroid cancer requires an appreciation of the pathophysiologic factors implicated in thyroid hyperplasia and neoplasia: growth factors (especially thyrotropin, TSH), growth-stimulating immunoglobulins, activating mutations of the TSH receptor, and other oncogenic transformations. In patients with diffuse goiter and thyroid nodules, serum TSH measurement in a highly sensitive assay excludes both primary hypothyroidism and common causes of thyrotoxicosis. In selected patients, screening for anti-thyroid peroxidase with or without anti-thyroglobulin antibodies can confirm the diagnosis of autoimmune thyroiditis. Serum calcitonin measurement is appropriate only when medullary thyroid carcinoma (MTC) is clinically suspected. Laboratory testing is essential in management of thyroid carcinoma patients after primary surgical therapy. Serum TSH measurement is vital to ensure that thyroxine replacement and TSH suppression are adequate in treatment of epithelial cancers. Serial monitoring of serum thyroglobulin (Tg) can detect tumor recurrence and quantify tumor burden. Interpretation of serum Tg results requires an appreciation of certain technical considerations (e.g., anti-Tg antibody interference) and the patient's concurrent TSH status. Periodic serum Tg measurements and 131I scans are complementary monitoring techniques. Serum calcitonin measurement and screening for ret protooncogene mutations are both valuable for identifying individuals with MTC.
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Sanchez-Martin, Marta, and Adolfo Ferrando. "The NOTCH1-MYC highway toward T-cell acute lymphoblastic leukemia." Blood 129, no. 9 (March 2, 2017): 1124–33. http://dx.doi.org/10.1182/blood-2016-09-692582.
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Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a highly proliferative hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation in T-ALL lymphoblasts are sustained by activation of strong oncogenic drivers promoting cell anabolism and cell cycle progression. Oncogenic NOTCH signaling, which is activated in more than 65% of T-ALL patients by activating mutations in the NOTCH1 gene, has emerged as a major regulator of leukemia cell growth and metabolism. T-ALL NOTCH1 mutations result in ligand-independent and sustained NOTCH1-receptor signaling, which translates into activation of a broad transcriptional program dominated by upregulation of genes involved in anabolic pathways. Among these, the MYC oncogene plays a major role in NOTCH1-induced transformation. As result, the oncogenic activity of NOTCH1 in T-ALL is strictly dependent on MYC upregulation, which makes the NOTCH1-MYC regulatory circuit an attractive therapeutic target for the treatment of T-ALL.
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Lim, Jonathan K. M., Alberto Delaidelli, Sean W. Minaker, Hai-Feng Zhang, Milena Colovic, Hua Yang, Gian Luca Negri, et al. "Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance." Proceedings of the National Academy of Sciences 116, no. 19 (April 18, 2019): 9433–42. http://dx.doi.org/10.1073/pnas.1821323116.
Full textAbstract:
The RAS family of proto-oncogenes are among the most commonly mutated genes in human cancers and predict poor clinical outcome. Several mechanisms underlying oncogenic RAS transformation are well documented, including constitutive signaling through the RAF-MEK-ERK proproliferative pathway as well as the PI3K-AKT prosurvival pathway. Notably, control of redox balance has also been proposed to contribute to RAS transformation. However, how homeostasis between reactive oxygen species (ROS) and antioxidants, which have opposing effects in the cell, ultimately influence RAS-mediated transformation and tumor progression is still a matter of debate and the mechanisms involved have not been fully elucidated. Here, we show that oncogenic KRAS protects fibroblasts from oxidative stress by enhancing intracellular GSH levels. Using a whole transcriptome approach, we discovered that this is attributable to transcriptional up-regulation of xCT, the gene encoding the cystine/glutamate antiporter. This is in line with the function of xCT, which mediates the uptake of cystine, a precursor for GSH biosynthesis. Moreover, our results reveal that the ETS-1 transcription factor downstream of the RAS-RAF-MEK-ERK signaling cascade directly transactivates the xCT promoter in synergy with the ATF4 endoplasmic reticulum stress-associated transcription factor. Strikingly, xCT was found to be essential for oncogenic KRAS-mediated transformation in vitro and in vivo by mitigating oxidative stress, as knockdown of xCT strongly impaired growth of tumor xenografts established from KRAS-transformed cells. Overall, this study uncovers a mechanism by which oncogenic RAS preserves intracellular redox balance and identifies an unexpected role for xCT in supporting RAS-induced transformation and tumorigenicity.
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Alema, S., F. Tato, and D. Boettiger. "myc and src oncogenes have complementary effects on cell proliferation and expression of specific extracellular matrix components in definitive chondroblasts." Molecular and Cellular Biology 5, no. 3 (March 1985): 538–44. http://dx.doi.org/10.1128/mcb.5.3.538-544.1985.
Full textAbstract:
The effects of the avian viral oncogenes src and myc were compared for their ability to alter the differentiated phenotype and the proliferative capacity of definitive chondroblasts. As previously demonstrated, viruses carrying the src oncogene suppressed the synthesis of the chondroblast-specific products, type II collagen and cartilage-specific sulfated proteoglycan. In contrast, infection with MC29 and HB1 viruses, which carry the myc oncogene, did not suppress the synthesis of these normal differentiated cell products, but the infected cells exhibited an increased proliferative potential. The MH2 virus, which carries both the myc and mil oncogenes, both induced the suppression of these chondroblast-specific products and increased cell proliferation. The implications of these results for cooperation between oncogenes and the multi-oncogene models for neoplastic transformation are discussed.
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Alema, S., F. Tato, and D. Boettiger. "myc and src oncogenes have complementary effects on cell proliferation and expression of specific extracellular matrix components in definitive chondroblasts." Molecular and Cellular Biology 5, no. 3 (March 1985): 538–44. http://dx.doi.org/10.1128/mcb.5.3.538.
Full textAbstract:
The effects of the avian viral oncogenes src and myc were compared for their ability to alter the differentiated phenotype and the proliferative capacity of definitive chondroblasts. As previously demonstrated, viruses carrying the src oncogene suppressed the synthesis of the chondroblast-specific products, type II collagen and cartilage-specific sulfated proteoglycan. In contrast, infection with MC29 and HB1 viruses, which carry the myc oncogene, did not suppress the synthesis of these normal differentiated cell products, but the infected cells exhibited an increased proliferative potential. The MH2 virus, which carries both the myc and mil oncogenes, both induced the suppression of these chondroblast-specific products and increased cell proliferation. The implications of these results for cooperation between oncogenes and the multi-oncogene models for neoplastic transformation are discussed.
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Seyedmehdi, Shojaee, Zhengshan Chen, Maike Buchner, Christian Hurtz, Huimin Geng, Hilde Schjerven, Lai N. Chan, et al. "Erk and Stat5 Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia." Blood 124, no. 21 (December 6, 2014): 787. http://dx.doi.org/10.1182/blood.v124.21.787.787.
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Abstract Background and Hypothesis: Targeted therapy of cancer typically focuses on the development of agents that will inactivate a transforming oncogene. In this study, we tested the concept that besides the oncogene itself, factors that enable permissiveness of a normal cell to oncogenic signaling represent a novel class of therapeutic targets. This hypothesis was based on three findings. First, acute activation of oncogenes in normal pre-B cells typically caused immediate cell death, unless pre-B cells were capable of adapting quickly enough to a high level of signaling output. Second, few surviving pre-B cell clones achieved permissiveness to oncogenic signaling by strong activation of negative feedback control of Erk and Stat5. Third, robust feedback control of Erk and Stat5 distinguishes normal pre-B cells from fully transformed pre-B acute lymphoblastic leukemia (ALL) cells. Results: To test the significance of strong feedback control of Erk and Stat5 signaling in pre-B ALL cells, we developed genetic loss-of function models for six central molecules in Erk (DUSP6, SPRY2, ETV5) and Stat5 (Cish, SOCS2, SOCS3) feedback control. Genetic deletion of the sprouty family Ras inhibitor Spry2, the Erk dual specificity phosphatase Dusp6 and their transcriptional activator Etv5, decreased robustness of Erk feedback control and compromised oncogenic transformation in mouse models for pre-B ALL. Likewise, ablation of Stat5 feedback control through deletion of the suppressors of cytokine signaling (SOCS) family molecules Cish, Socs2 and Socs3 reversed permissiveness of pre-B cells. Studying deletion of Spry2 (Erk) and Cish (Stat5) in an in vivo transplant model using inducible, Cre-mediated deletion of Spry2 and Cish in pre-B ALL cells confirmed that Erk and Stat5 feedback control are essential for malignant transformation and development of lethal leukemia. Genetic deletion of Erk (Dusp6, Spry2, Etv5) and Stat5 (Cish, Socs2, Socs3) feedback control impairs leukemic transformation of pre-B cells. Searching for factors that restrict permissiveness to oncogene signaling, we identified the pre-B cell tumor suppressor IKZF1, which is deleted in a large fraction of pre-B ALL cases. IKZF1 directly bound to and transcriptionally repressed multiple promoters of Erk and Stat5 feedback control and IKZF1 deletion raised the limit of maximum allowable oncogene signaling strength in pre-B ALL cells. We propose that the pre-B cell tumor suppressor IKZF1 functions as transcriptional repressor of Erk and Stat5 feedback control and thereby retains pre-B cells in a Non-permissive state. Clinical relevance: To assess potential usefulness of this finding for the development of future treatment strategies, we tested the effect of a specific small molecule inhibitor of DUSP6, E-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), which was designed as an allosteric inhibitor of the interaction between DUSP6 and phospho-ERK1/2. Interestingly, BCI acutely subverted Erk feedback control and selectively induced cell death in pre-B ALL cells. Small molecule inhibition of DUSP6 was sufficient to overcome conventional mechanisms of drug-resistance in pre-B ALL and selectively killed patient-derived pre-B ALL cells in a leukemia transplant model. BCI treatment, similar to Dusp6-deletion in our leukemia mouse model, led to the accumulation of P53 and ARF in patient-derived pre-B ALL cells. In addition, small molecule inhibition of DUSP6 had strong selective activity on drug-resistant patient-derived pre-B ALL cells that were injected into NOD/SCID transplant recipient mice. These findings identify permissive negative feedback control of oncogenic signaling as a previously unrecognized vulnerability of pre-B ALL cells and a new class of potential therapeutic targets. Conclusion: Targeting negative feedback regulation of both Erk and Stat5 signaling for the treatment of pre-B ALL seems counter-intuitive because it represents effectively the opposite of current efforts of targeted inhibition of oncogenic signaling. Our results, however, demonstrate that a robust negative feedback regulation is required for the leukemic transformation and development of fatal leukemia in pre-B ALL. We demonstrate that feedback control of Erk and Stat5 signaling represents a previously unrecognized vulnerability and, potentially, a novel class of therapeutic targets in human pre-B ALL. Disclosures No relevant conflicts of interest to declare.
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Mumby, M. C., and G. Walter. "Protein phosphatases and DNA tumor viruses: transformation through the back door?" Cell Regulation 2, no. 8 (August 1991): 589–98. http://dx.doi.org/10.1091/mbc.2.8.589.
Full textAbstract:
Cellular transformation by many oncogenic viruses is mediated by alterations in signal transduction pathways that control normal growth and proliferation. Common targets for many transforming viruses are pathways regulated by protein phosphorylation. The biochemical control of proteins in these pathways is a dynamic process that is regulated by the relative activities of protein kinases and phosphatases. Although there are numerous examples of viral oncogenes that encode protein kinases (Hunter, 1991), until recently there has been no evidence linking altered phosphatase activity to transformation. In this review we describe a novel mechanism, utilized by small DNA tumor viruses, in which viral oncogenes bind to and regulate a cellular protein serine/threonine phosphatase. The currently available evidence indicates that alteration of phosphatase activity and subsequent changes in phosphorylation levels is an important step in transformation by these viruses.
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Sulis, Maria Luisa, Teresa Palomero, Pedro J. Real, Kelly C. Barnes, Peter Aplan, Neal Copeland, Dave Utpal, et al. "Identification of Oncogenic Pathways of T-Acute Lymphoblastic Leukemia (T-ALL) through Gene Expression Profiling of Mouse Tumor Models." Blood 108, no. 11 (November 1, 2006): 2234. http://dx.doi.org/10.1182/blood.v108.11.2234.2234.
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Abstract Transgenic mouse models of T-cell oncogenes such as TAL1 and LMO1, have confirmed their critical role in the development of T-lymphoblastic lymphoma (T-LL). In addition, retroviral insertional mutagenesis (RIM) in mice is a powerful system for the identification of genes involved in T-cells leukemogenesis. However, incomplete knowledge of the pathogenesis of T-ALL limits the ability to stratify patients and to deliver tailored therapy accordingly. Thus, a major goal is to identify common oncogenic pathways downstream of T-cell oncogenes that can serve as therapeutic targets for the treatment of T-ALL. We hypothesize that T-cell oncogenes operate through a limited number of oncogenic pathways with distinct gene expression profiles. Furthermore, we propose that gene expression profiling of murine models of T-cell lymphomas, which harbor specific genetic lesions, will serve to identify such oncogenic pathways and to establish a molecular classification of T-ALL. To test this hypothesis we have analyzed normal thymus and mouse T-cell lymphomas originated from retroviral insertional mutagenesis (n=11) and transgenic and knock-outs models (n=30) using Affymetrix 430A2.0 microarrays. Unsupervised analysis clearly distinguishes tumor samples from normal thymus and clusters the tumors into three major groups. TAL1, LMO2 and E2 proteins are known to be part of a transcriptional complex and to cooperate in T-cell leukemogenesis by suppressing E2A function. Accordingly, mouse tumors originating in TAL1, TAL1/LMO2 transgenic and E2A knock-out mice share a common gene expression signature and cluster together. Supervised analysis of tumors generated by retroviral mutagenesis showed increased expression of the proviral tagged genes and identified corresponding known downstream targets. Nearest neighbor analysis identified high levels of Notch1 expression in tumors with proviral insertion in the Notch1 locus and in tumors generated in the TAL1/, TAL1/LMO2, OLIG2/LMO1, ThPOK and Ikaros mouse models, which harbored activating mutations in NOTCH1. Our results demonstrate that gene expression profiling identifies common oncogenic pathways in T-cell tumors generated in mice, establishes common mechanisms of transformation for several T-ALL oncogenes and allows coupling of poorly characterized genes identified in proviral insertional sites with well characterized oncogenes and downstream molecular pathways. The identification of mechanisms of T-cell transformation common to tumors of different origin lays the ground for the identification of new therapeutic targets for the treatment of T-ALL.
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Pandya, Jyotsna, and Dennis M. Walling. "Oncogenic Activity of Epstein-Barr Virus Latent Membrane Protein 1 (LMP-1) Is Down-Regulated by Lytic LMP-1." Journal of Virology 80, no. 16 (August 15, 2006): 8038–46. http://dx.doi.org/10.1128/jvi.00180-06.
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ABSTRACT The Epstein-Barr virus (EBV) is an oncogenic human herpesvirus. EBV latent membrane protein 1 (LMP-1) is a viral oncogene that manifests its oncogenic phenotype through activation of cellular signaling pathways involved in cell growth, survival, differentiation, and transformation. Lytic LMP-1 (lyLMP-1) is a related EBV gene without oncogenic properties. The lyLMP-1 gene is found in 60% of the EBV strains circulating in nature, but it is not found in EBV strains associated with nasopharyngeal carcinoma. We recently demonstrated that lyLMP-1 down-regulates the half-life of LMP-1 in epithelial cells. Therefore in this study, we tested the hypothesis that lyLMP-1 concomitantly down-regulates LMP-1 oncogenic activity. The results demonstrated that lyLMP-1 inhibits LMP-1-mediated intracellular signaling activation, epithelial cell growth and survival, and fibroblast cell transformation in a dose-dependent manner. Lytic LMP-1 manifested this effect through the promotion of LMP-1 degradation and a reduction in the expressed quantity of LMP-1. Thus, lyLMP-1 functions as a posttranslational negative regulator of LMP-1 oncogenesis. These results support a model of EBV-associated epithelial oncogenesis in which lyLMP-1 may act in vivo to reduce the risk of LMP-1-mediated transformation and is therefore subjected to negative selection in nasopharyngeal carcinoma pathogenesis.