Journal articles: 'Oncogenic protein'

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Rodrigues, G. A., and M. Park. "Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase." Molecular and Cellular Biology 13, no. 11 (November 1993): 6711–22. http://dx.doi.org/10.1128/mcb.13.11.6711-6722.1993.

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Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed.

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Rodrigues, G. A., and M. Park. "Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase." Molecular and Cellular Biology 13, no. 11 (November 1993): 6711–22. http://dx.doi.org/10.1128/mcb.13.11.6711.

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Oncogenic activation of the met (hepatocyte growth factor/scatter factor) receptor tyrosine kinase involves a genomic rearrangement that generates a hybrid protein containing tpr-encoded sequences at its amino terminus fused directly to the met-encoded receptor kinase domain. Deletion of Tpr sequences abolishes the transforming ability of this protein, implicating this region in oncogenic activation. We demonstrate, by site-directed mutagenesis and coimmunoprecipitation experiments, that a leucine zipper motif within Tpr mediates dimerization of the tpr-met product and is essential for the transforming activity of the met oncogene. By analogy with ligand-stimulated activation of receptor tyrosine kinases, we propose that constitutive dimerization mediated by a leucine zipper motif within Tpr is responsible for oncogenic activation of the Met kinase. The possibility that this mechanism of activation represents a paradigm for a class of receptor tyrosine kinase oncogenes activated by DNA rearrangement is discussed.

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Cai, Mei, Joseph Amor, and Maiyon Park. "Abstract 5834: Examining the potential oncogenic function of septins and their interaction with Chmp1A tumor suppressor in pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5834. http://dx.doi.org/10.1158/1538-7445.am2022-5834.

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Abstract Introduction: Chmp1A functions as a tumor suppressor by the activation of ATM and p53 in pancreatic cancer. The nuclear localization signal (NLS) of Chmp1A is required for cell growth inhibition and activation of ATM and p53. Proteomic analysis has identified Septins (a group of GTP-binding proteins) to be associated with the NLS-deleted Chmp1A. Since NLS-deleted Chmp1A promotes cancer cell growth, we hypothesized that Septins may function as oncogenes and that Chmp1A functions as a tumor suppressor partly by inhibiting the oncogenic action of Septin proteins. Objective: To examine whether Septin proteins exhibit oncogenic activity and to investigate whether Chmp1A inhibits the oncogenic function of Septins. Methodology: Using normal pancreatic and cancer cells, we compared Septin transcripts using PCR assays, Septin protein expression using Western blot, and Septin cellular expression using immunocytochemistry. We performed immunohistochemical analysis to examine whether Septin expression is increased in pancreatic cancer tissues compared to corresponding normal tissues. Silencing technology was used to test whether Septin expression is regulated by Chmp1A. Results: Our preliminary data indicates that the transcript and protein of Septins are increased in various pancreatic cancer cell lines compared to normal. Septin protein expression was increased or altered in human pancreatic ductal adenocarcinoma tissues compared to corresponding normal tissues. Additionally, our data implies that Chmp1A negatively regulates Septin expression, since Septin transcripts and proteins are increased when Chmp1A protein is silenced. Summary and future direction: Our data suggests that Septin functions as an oncogene in pancreatic cancer cells and that Chmp1A functions as a tumor suppressor partly by inhibiting the oncogenic action of Septin proteins. For the completion of the project in the future, we plan to confirm the function of Septins by investigating the effect of Septin overexpression on pancreatic cancer cell proliferation. In addition, we will further investigate the interaction between Septins and Chmp1A by examining Septin expression and localization in pancreatic cancer cells that overexpress Chmp1A. Citation Format: Mei Cai, Joseph Amor, Maiyon Park. Examining the potential oncogenic function of septins and their interaction with Chmp1A tumor suppressor in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5834.

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Longo, Dan L., and Neal Rosen. "Targeting Oncogenic RAS Protein." New England Journal of Medicine 387, no. 2 (July 14, 2022): 184–86. http://dx.doi.org/10.1056/nejme2206831.

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Gambacorti-Passerini, C. "Oncogenic protein tyrosine kinases." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2895–96. http://dx.doi.org/10.1007/s00018-004-4270-1.

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Saglio, G., and D. Cilloni. "Oncogenic protein tyrosine kinases." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2897–911. http://dx.doi.org/10.1007/s00018-004-4271-0.

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Jones, A. V., and N. C. P. Cross. "Oncogenic protein tyrosine kinases." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2912–23. http://dx.doi.org/10.1007/s00018-004-4272-z.

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Kitamura, Y., and S. Hirotab. "Oncogenic protein tyrosine kinases." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2924–31. http://dx.doi.org/10.1007/s00018-004-4273-y.

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Naoe, T., and H. Kiyoi. "Oncogenic protein tyrosine kinases." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2932–38. http://dx.doi.org/10.1007/s00018-004-4274-x.

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Pulford, K., L. Lamant, E. Espinos, Q. Jiang, L. Xue, F. Turturro, G. Delsol, and S. W. Morris. "Oncogenic protein tyrosine kinases." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2939–53. http://dx.doi.org/10.1007/s00018-004-4275-9.

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Santoro, M., F. Carlomagno, R. M. Melillo, and A. Fusco. "Oncogenic protein tyrosine kinases." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2954–64. http://dx.doi.org/10.1007/s00018-004-4276-8.

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M�nard, S., P. Casalini, M. Campiglio, S. M. Pupa, and E. Tagliabue. "Oncogenic protein tyrosine kinases." Cellular and Molecular Life Sciences 61, no. 23 (December 2004): 2965–78. http://dx.doi.org/10.1007/s00018-004-4277-7.

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Gabai, Vladimir L., Julia A. Yaglom, Todd Waldman, and Michael Y. Sherman. "Heat Shock Protein Hsp72 Controls Oncogene-Induced Senescence Pathways in Cancer Cells." Molecular and Cellular Biology 29, no. 2 (November 10, 2008): 559–69. http://dx.doi.org/10.1128/mcb.01041-08.

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ABSTRACT The heat shock protein Hsp72 is expressed at the elevated levels in various human tumors, and its levels often correlate with poor prognosis. Previously we reported that knockdown of Hsp72 in certain cancer cells, but not in untransformed breast epithelial cells, triggers senescence via p53-dependent and p53-independent mechanisms. Here we demonstrate that the p53-dependent pathway controlled by Hsp72 depends on the oncogenic form of phosphatidylinositol 3-kinase (PI3K). Indeed, upon expression of the oncogenic PI3K, epithelial cells began responding to Hsp72 depletion by activating the p53 pathway. Moreover, in cancer cell lines, activation of the p53 pathway caused by depletion of Hsp72 was dependent on oncogenes that activate the PI3K pathway. On the other hand, the p53-independent senescence pathway controlled by Hsp72 was associated with the Ras oncogene. In this pathway, extracellular signal-regulated kinases (ERKs) were critical for senescence, and Hsp72 controlled the ERK-activating kinase cascade at the level of Raf-1. Importantly, upon Ras expression, untransformed cells started responding to knockdown of Hsp72 by constitutive activation of ERKs, culminating in senescence. Therefore, Hsp72 is intimately involved in suppression of at least two separate senescence signaling pathways that are regulated by distinct oncogenes in transformed cells, which explains why cancer cells become “addicted” to this heat shock protein.

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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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Gaudio, Eugenio, Francesco Paduano, Apollinaire Ngankeu, Francesca Lovat, Muller Fabbri, Hui-Lung Sun, Pierluigi Gasparini, et al. "Heat shock protein 70 regulates Tcl1 expression in leukemia and lymphomas." Blood 121, no. 2 (January 10, 2013): 351–59. http://dx.doi.org/10.1182/blood-2012-09-457374.

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Abstract T-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated. The association of Tcl1 and Ataxia Telangiectasia Mutated leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with heat shock protein (Hsp) 70. The Tcl1-Hsp70 complex was validated by coimmunoprecipitation experiments. In addition, we report that Hsp70, a protein that plays a critical role in the folding and maturation of several oncogenic proteins, associates with Tcl1 protein and stabilizes its expression. The inhibition of the ATPase activity of Hsp70 results in ubiquitination and proteasome-dependent degradation of Tcl1. The inhibition of Hsp70 significantly reduced the growth of lymphoma xenografts in vivo and down-regulated the expression of Tcl1 protein. Our findings reveal a functional interaction between Tcl1 and Hsp70 and identify Tcl1 as a novel Hsp70 client protein. These findings suggest that inhibition of Hsp70 may represent an alternative effective therapy for chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.

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Qiu, Bo, Bo Qiu, and Bo Qiu. "TMOD-27. IDENTIFYING ONCOGENIC C-MYC AND MYCN COMPLEXES IN HIGH-RISK PEDIATRIC CANCERS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi221. http://dx.doi.org/10.1093/neuonc/noab196.888.

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Abstract The MYC family of proto-oncogenes is activated in a variety of cancers, including multiple high-risk pediatric malignancies. c-MYC (MYC) is ubiquitously expressed in human tissues, while MYCN (MYCN) has tissue and developmentally restricted expression patterns. In both neuroblastoma and medulloblastoma, enhanced activity of either MYCN or c-MYC drives high-risk disease. As transcription factors, MYC proteins exert oncogenic functions through protein-protein interaction networks that alter gene expression, but also mediate a growing list of target-gene independent nuclear functions (transcriptional elongation, chromatin changes throughout the cell cycle, etc…). While c-MYC and MYCN share many functions, they also regulate distinct cellular processes, and within medulloblastoma, they are activated in distinct molecular sub-groups (i.e. MYCN amplification is found in aggressive sonic hedge hog (SHH) subgroup tumors, while MYC amplification is found in aggressive group 3 and group 4 tumors). Here, we present an approach to identify oncogenic functions of c-MYC and MYCN in medulloblastoma and neuroblastoma using human induced pluripotent stem cell (iPSCO based orthotopic model systems. We hypothesize that the protein interaction networks and oncogenic functions of c-MYC and MYCN are impacted by cellular context, which are recapitulated in our orthotopic models (cell transcriptional and epigenetic landscape, tumor microenvironment). This premise is supported by recent single cell sequencing efforts in medulloblastoma and neuroblastoma, where primary human tumor cells are found to recapitulate specific transcriptional cell states found in normal hindbrain and sympathetic nervous system development, respectively. Through proximity labeling and quantitative mass spectrometry, we aim to identify tumor and oncogene specific protein interaction networks. This information will guide functional screening approaches to identify tumor-specific vulnerabilities. * Note MYC(N) refers to c-MYC and MYCN.

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Kamens, J., P. Richardson, G. Mosialos, R. Brent, and T. Gilmore. "Oncogenic transformation by vrel requires an amino-terminal activation domain." Molecular and Cellular Biology 10, no. 6 (June 1990): 2840–47. http://dx.doi.org/10.1128/mcb.10.6.2840-2847.1990.

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The mechanism by which the products of the v-rel oncogene, the corresponding c-rel proto-oncogene, and the related dorsal gene of Drosophila melanogaster exert their effects is not clear. Here we show that the v-rel, chicken c-rel, and dorsal proteins activated gene expression when fused to LexA sequences and bound to DNA upstream of target genes in Saccharomyces cerevisiae. We have defined two distinct activation regions in the c-rel protein. Region I, located in the amino-terminal half of rel and dorsal proteins, contains no stretches of glutamines, prolines, or acidic amino acids and therefore may be a novel activation domain. Lesions in the v-rel protein that diminished or abolished oncogenic transformation of avian spleen cells correspondingly affected transcription activation by region I. Region II, located in the carboxy terminus of the c-rel protein, is highly acidic. Region II is not present in the v-rel protein or in a transforming mutant derivative of the c-rel protein. Our results show that the oncogenicity of Rel proteins requires activation region I and suggest that the biological function of rel and dorsal proteins depends on transcription activation by this region.

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Kamens, J., P. Richardson, G. Mosialos, R. Brent, and T. Gilmore. "Oncogenic transformation by vrel requires an amino-terminal activation domain." Molecular and Cellular Biology 10, no. 6 (June 1990): 2840–47. http://dx.doi.org/10.1128/mcb.10.6.2840.

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The mechanism by which the products of the v-rel oncogene, the corresponding c-rel proto-oncogene, and the related dorsal gene of Drosophila melanogaster exert their effects is not clear. Here we show that the v-rel, chicken c-rel, and dorsal proteins activated gene expression when fused to LexA sequences and bound to DNA upstream of target genes in Saccharomyces cerevisiae. We have defined two distinct activation regions in the c-rel protein. Region I, located in the amino-terminal half of rel and dorsal proteins, contains no stretches of glutamines, prolines, or acidic amino acids and therefore may be a novel activation domain. Lesions in the v-rel protein that diminished or abolished oncogenic transformation of avian spleen cells correspondingly affected transcription activation by region I. Region II, located in the carboxy terminus of the c-rel protein, is highly acidic. Region II is not present in the v-rel protein or in a transforming mutant derivative of the c-rel protein. Our results show that the oncogenicity of Rel proteins requires activation region I and suggest that the biological function of rel and dorsal proteins depends on transcription activation by this region.

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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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Pincus, Matthew R., Bo Lin, Purvi Patel, Elmer Gabutan, Nitzan Zohar, and Wilbur B. Bowne. "Peptides That Block RAS-p21 Protein-Induced Cell Transformation." Biomedicines 11, no. 2 (February 6, 2023): 471. http://dx.doi.org/10.3390/biomedicines11020471.

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This is a review of approaches to the design of peptides and small molecules that selectively block the oncogenic RAS-p21 protein in ras-induced cancers. Single amino acid substitutions in this protein, at critical positions such as at Gly 12 and Gln 61, cause the protein to become oncogenic. These mutant proteins cause over 90 percent of pancreatic cancers, 40–50 percent of colon cancers and about one third of non-small cell cancers of the lung (NSCCL). RAS-p21 is a G-protein that becomes activated when it exchanges GDP for GTP. Several promising approaches have been developed that target mutant (oncogenic) RAS-p21 proteins in these different cancers. These approaches comprise: molecular simulations of mutant and wild-type proteins to identify effector domains, for which peptides can be made that selectively inhibit the oncogenic protein that include PNC-1 (ras residues 115–126), PNC-2 (ras residues 96–110) and PNC7 (ras residues 35–47); the use of contiguous RAS-p21 peptide sequences that can block ras signaling; cyclic peptides from large peptide libraries and small molecule libraries that can be identified in high throughput assays that can selectively stabilize inactive forms of RAS-p21; informatic approaches to discover peptides and small molecules that dock to specific domains of RAS-p21 that can block mitogenic signal transduction by oncogenic RAS-p21; and the use of cell-penetrating peptides (CPPs) that are attached to the variable domains of the anti-RAS-p21 inactivating monoclonal antibody, Y13 259, that selectively enters oncogenic RAS-p21-containing cancer cells, causing these cells to undergo apoptosis. Several new anti-oncogenic RAS-p21 agents, i.e., Amgen’s AMG510 and Mirati Therapeutics’ MRTX849, polycyclic aromatic compounds, have recently been FDA-approved and are already being used clinically to treat RAS-p21-induced NSCCL and colorectal carcinomas. These new drugs target the inactive form of RAS-p21 bound to GDP with G12C substitution at the critical Gly 12 residue by binding to a groove bordered by specific domains in this mutant protein into which these compounds insert, resulting in the stabilization of the inactive GDP-bound form of RAS-p21. Other peptides and small molecules have been discovered that block the G12D-RAS-p21 oncogenic protein. These agents can treat specific mutant protein-induced cancers and are excellent examples of personalized medicine. However, many oncogenic RAS-p21-induced tumors are caused by other mutations at positions 12, 13 and 61, requiring other, more general anti-oncogenic agents that are being provided using alternate methods.

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Druillennec, Sabine, Coralie Dorard, and Alain Eychène. "Alternative Splicing in Oncogenic Kinases: From Physiological Functions to Cancer." Journal of Nucleic Acids 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/639062.

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Among the 518 protein kinases encoded by the human kinome, several of them act as oncoproteins in human cancers. Like other eukaryotic genes, oncogenes encoding protein kinases are frequently subjected to alternative splicing in coding as well as noncoding sequences. In the present paper, we will illustrate how alternative splicing can significantly impact on the physiological functions of oncogenic protein kinases, as demonstrated by mouse genetic model studies. This includes examples of membrane-bound tyrosine kinases receptors (FGFR2, Ret, TrkB, ErbB4, and VEGFR) as well as cytosolic protein kinases (B-Raf). We will further discuss how regular alternative splicing events of these kinases are in some instances implicated in oncogenic processes during tumor progression (FGFR, TrkB, ErbB2, Abl, and AuroraA). Finally, we will present typical examples of aberrant splicing responsible for the deregulation of oncogenic kinases activity in cancers (AuroraB, Jak2, Kit, Met, and Ron).

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Danilkovitch-Miagkova, Alla, Alexei Miagkov, Alison Skeel, Noboru Nakaigawa, Berton Zbar, and Edward J. Leonard. "Oncogenic Mutants of RON and MET Receptor Tyrosine Kinases Cause Activation of the β-Catenin Pathway." Molecular and Cellular Biology 21, no. 17 (September 1, 2001): 5857–68. http://dx.doi.org/10.1128/mcb.21.17.5857-5868.2001.

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ABSTRACT β-Catenin is an oncogenic protein involved in regulation of cell-cell adhesion and gene expression. Accumulation of cellular β-catenin occurs in many types of human cancers. Four mechanisms are known to cause increases in β-catenin: mutations of β-catenin, adenomatous polyposis coli, or axin genes and activation of Wnt signaling. We report a new cause of β-catenin accumulation involving oncogenic mutants of RON and MET receptor tyrosine kinases (RTKs). Cells transfected with oncogenic RON or MET were characterized by β-catenin tyrosine phosphorylation and accumulation; constitutive activation of a Tcf transcriptional factor; and increased levels of β-catenin/Tcf target oncogene proteins c-mycand cyclin D1. Interference with the β-catenin pathway reduced the transforming potential of mutated RON and MET. Activation of β-catenin by oncogenic RON and MET constitutes a new pathway, which might lead to cell transformation by these and other mutant growth factor RTKs.

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Yokoyama, Akihiko, Tim Somervaille, and Michael L. Cleary. "The Menin Tumor Suppressor Protein Is an Essential Oncogenic Cofactor for MLL-Associated Leukemogenesis." Blood 106, no. 11 (November 16, 2005): 665. http://dx.doi.org/10.1182/blood.v106.11.665.665.

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Abstract The Mixed Lineage Leukemia (MLL) protein is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. MLL normally associates with a cohort of highly conserved cofactors to form a macromolecular complex that includes menin, a product of the MEN1 tumor suppressor gene, which is mutated in heritable and sporadic endocrine tumors. We demonstrate here that oncogenic MLL fusion proteins retain an ability to stably associate with menin through a high-affinity, amino-terminal, conserved binding motif and that this interaction is required for the initiation of MLL-mediated leukemogenesis. Furthermore, menin is essential for maintenance of MLL-associated but not other oncogene induced myeloid transformation. Acute genetic ablation of menin reverses aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes, and specifically abrogates the differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. These results demonstrate that a human oncoprotein is critically dependent on direct physical interaction with a tumor suppressor protein for its oncogenic activity, validate a potential target for molecular therapy, and suggest central roles for menin in altered epigenetic functions underlying the pathogenesis of hematopoietic cancers.

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Nevels, Michael, Birgitt Täuber, Elisabeth Kremmer, Thilo Spruss, Hans Wolf, and Thomas Dobner. "Transforming Potential of the Adenovirus Type 5 E4orf3 Protein." Journal of Virology 73, no. 2 (February 1, 1999): 1591–600. http://dx.doi.org/10.1128/jvi.73.2.1591-1600.1999.

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ABSTRACT Previous observations that the adenovirus type 5 (Ad5) E4orf6 and E4orf3 gene products have redundant effects in viral lytic infection together with the recent findings that E4orf6 possesses transforming potential prompted us to investigate the effect of E4orf3 expression on the transformation of primary rat cells in combination with adenovirus E1 oncogene products. Our results demonstrate for the first time that E4orf3 can cooperate with adenovirus E1A and E1A plus E1B proteins to transform primary baby rat kidney cells, acting synergistically with E4orf6 in the presence of E1B gene products. Transformed rat cells expressing E4orf3 exhibit morphological alterations, higher growth rates and saturation densities, and increased tumorigenicity compared with transformants expressing E1 proteins only. Consistent with previous results for adenovirus-infected cells, the E4orf3 protein is immunologically restricted to discrete nuclear structures known as PML oncogenic domains (PODs) in transformed rat cells. As opposed to E4orf6, the ability of E4orf3 to promote oncogenic cell growth is probably not linked to a modulation of p53 functions and stability. Instead, our results indicate that the transforming activities of E4orf3 are due to combinatorial effects that involve the binding to the adenovirus 55-kDa E1B protein and the colocalization with PODs independent from interactions with the PML gene product. These data fit well with a model in which the reorganization of PODs may trigger a cascade of processes that cause uncontrolled cell proliferation and neoplastic growth. In sum, our results provide strong evidence for the idea that interactions with PODs by viral proteins are linked to oncogenic transformation.

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Lederer, Marcell, Simon Müller, Markus Glaß, Nadine Bley, Christian Ihling, Andrea Sinz, and Stefan Hüttelmaier. "Oncogenic Potential of the Dual-Function Protein MEX3A." Biology 10, no. 5 (May 7, 2021): 415. http://dx.doi.org/10.3390/biology10050415.

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MEX3A belongs to the MEX3 (Muscle EXcess) protein family consisting of four members (MEX3A-D) in humans. Characteristic for MEX3 proteins is their domain structure with 2 HNRNPK homology (KH) domains mediating RNA binding and a C-terminal really interesting new gene (RING) domain that harbors E3 ligase function. In agreement with their domain composition, MEX3 proteins were reported to modulate both RNA fate and protein ubiquitination. MEX3 paralogs exhibit an oncofetal expression pattern, they are severely downregulated postnatally, and re-expression is observed in various malignancies. Enforced expression of MEX3 proteins in various cancers correlates with poor prognosis, emphasizing their oncogenic potential. The latter is supported by MEX3A’s impact on proliferation, self-renewal as well as migration of tumor cells in vitro and tumor growth in xenograft studies.

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Wheeler, D. B., R. Zoncu, D. E. Root, D. M. Sabatini, and C. L. Sawyers. "Identification of an oncogenic RAB protein." Science 350, no. 6257 (September 3, 2015): 211–17. http://dx.doi.org/10.1126/science.aaa4903.

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Hirai, Hisamaru, Koji Izutsu, Mineo Kurokawa, and Kinuko Mitani. "Oncogenic mechanisms of Evi-1 protein." Cancer Chemotherapy and Pharmacology 48 (July 1, 2001): S35—S40. http://dx.doi.org/10.1007/s002800100303.

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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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Sivaganesh, Vignesh, Varsha Sivaganesh, Christina Scanlon, Alexander Iskander, Salma Maher, Thư Lê, and Bela Peethambaran. "Protein Tyrosine Phosphatases: Mechanisms in Cancer." International Journal of Molecular Sciences 22, no. 23 (November 28, 2021): 12865. http://dx.doi.org/10.3390/ijms222312865.

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Protein tyrosine kinases, especially receptor tyrosine kinases, have dominated the cancer therapeutics sphere as proteins that can be inhibited to selectively target cancer. However, protein tyrosine phosphatases (PTPs) are also an emerging target. Though historically known as negative regulators of the oncogenic tyrosine kinases, PTPs are now known to be both tumor-suppressive and oncogenic. This review will highlight key protein tyrosine phosphatases that have been thoroughly investigated in various cancers. Furthermore, the different mechanisms underlying pro-cancerous and anti-cancerous PTPs will also be explored.

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Fahrmann, Johannes F., Hiroyuki Katayama, Ehsan Irajizad, Ashish Chakraborty, Taketo Kato, Xiangying Mao, Soyoung Park, et al. "Plasma Based Protein Signatures Associated with Small Cell Lung Cancer." Cancers 13, no. 16 (August 6, 2021): 3972. http://dx.doi.org/10.3390/cancers13163972.

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Small-cell-lung cancer (SCLC) is associated with overexpression of oncogenes including Myc family genes and YAP1 and inactivation of tumor suppressor genes. We performed in-depth proteomic profiling of plasmas collected from 15 individuals with newly diagnosed early stage SCLC and from 15 individuals before the diagnosis of SCLC and compared findings with plasma proteomic profiles of 30 matched controls to determine the occurrence of signatures that reflect disease pathogenesis. A total of 272 proteins were elevated (area under the receiver operating characteristic curve (AUC) ≥ 0.60) among newly diagnosed cases compared to matched controls of which 31 proteins were also elevated (AUC ≥ 0.60) in case plasmas collected within one year prior to diagnosis. Ingenuity Pathway analyses of SCLC-associated proteins revealed enrichment of signatures of oncogenic MYC and YAP1. Intersection of proteins elevated in case plasmas with proteomic profiles of conditioned medium from 17 SCLC cell lines yielded 52 overlapping proteins characterized by YAP1-associated signatures of cytoskeletal re-arrangement and epithelial-to-mesenchymal transition. Among samples collected more than one year prior to diagnosis there was a predominance of inflammatory markers. Our integrated analyses identified novel circulating protein features in early stage SCLC associated with oncogenic drivers.

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Peace, D. J., J. W. Smith, W. Chen, S. G. You, W. L. Cosand, J. Blake, and M. A. Cheever. "Lysis of ras oncogene-transformed cells by specific cytotoxic T lymphocytes elicited by primary in vitro immunization with mutated ras peptide." Journal of Experimental Medicine 179, no. 2 (February 1, 1994): 473–79. http://dx.doi.org/10.1084/jem.179.2.473.

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Ras protooncogenes are activated by characteristic point mutations in a wide variety of malignancies. The expressed p21ras proteins are oncogenic by virtue of single substituted amino acids, usually at position 12 or 61 of the 189-residue p21ras protein. In the current study, the ability of class I major histocompatibility complex (MHC)-restricted T cells to recognize the altered segment of a transforming p21ras protein and to lyse cells transformed by the corresponding ras oncogene was examined. Synthetic ras peptides encompassing the common activating substitution of leucine for glutamine at position 61 were constructed with an amino acid motif appropriate for binding to the H-2Kb murine class I MHC molecule. Cytotoxic T lymphocytes (CTL) specific for bound ras leucine 61 peptide were elicited by in vitro immunization of normal lymphocytes with synthetic peptides. The ras peptide-induced CTL specifically lysed syngeneic fibroblasts transformed by an activated ras gene encoding oncogenic p21ras protein containing the same single amino acid substitution. Thus, in some circumstances, mutated p21ras protein can serve as a tumor-specific antigen.

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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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Lovino, Marta, Gianvito Urgese, Enrico Macii, Santa Di Cataldo, and Elisa Ficarra. "A Deep Learning Approach to the Screening of Oncogenic Gene Fusions in Humans." International Journal of Molecular Sciences 20, no. 7 (April 2, 2019): 1645. http://dx.doi.org/10.3390/ijms20071645.

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Gene fusions have a very important role in the study of cancer development. In this regard, predicting the probability of protein fusion transcripts of developing into a cancer is a very challenging and yet not fully explored research problem. To this date, all the available approaches in literature try to explain the oncogenic potential of gene fusions based on protein domain analysis, that is cancer-specific and not easy to adapt to newly developed information. In our work, we choose the raw protein sequences as the input baseline, and propose the use of deep learning, and more specifically Convolutional Neural Networks, to infer the oncogenity probability score of gene fusion transcripts and to group them into a number of categories (e.g., oncogenic/not oncogenic). This is an inherently flexible methodology that, unlike previous approaches, can be re-trained with very less efforts on newly available data (for example, from a different cancer). Based on experimental results on a large dataset of pre-annotated gene fusions, our method is able to predict the oncogenity potential of gene fusion transcripts with accuracy of about 72%, which increases to 86% if we consider the only instances that are classified with a high confidence level.

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Wilmerding, Axelle, Lauranne Bouteille, Lucrezia Rinaldi, Nathalie Caruso, Yacine Graba, and Marie-Claire Delfini. "HOXB8 Counteracts MAPK/ERK Oncogenic Signaling in a Chicken Embryo Model of Neoplasia." International Journal of Molecular Sciences 22, no. 16 (August 18, 2021): 8911. http://dx.doi.org/10.3390/ijms22168911.

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HOX transcription factors are members of an evolutionarily conserved family of proteins required for the establishment of the anteroposterior body axis during bilaterian development. Although they are often deregulated in cancers, the molecular mechanisms by which they act as oncogenes or tumor suppressor genes are only partially understood. Since the MAPK/ERK signaling pathway is deregulated in most cancers, we aimed at apprehending if and how the Hox proteins interact with ERK oncogenicity. Using an in vivo neoplasia model in the chicken embryo consisting in the overactivation of the ERK1/2 kinases in the trunk neural tube, we analyzed the consequences of the HOXB8 gain of function at the morphological and transcriptional levels. We found that HOXB8 acts as a tumor suppressor, counteracting ERK-induced neoplasia. The HOXB8 tumor suppressor function relies on a large reversion of the oncogenic transcriptome induced by ERK. In addition to showing that the HOXB8 protein controls the transcriptional responsiveness to ERK oncogenic signaling, our study identified new downstream targets of ERK oncogenic activation in an in vivo context that could provide clues for therapeutic strategies.

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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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Kamata, T., and H. F. Kung. "Modulation of maturation and ribosomal protein S6 phosphorylation in Xenopus oocytes by microinjection of oncogenic ras protein and protein kinase C." Molecular and Cellular Biology 10, no. 3 (March 1990): 880–86. http://dx.doi.org/10.1128/mcb.10.3.880-886.1990.

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Using Xenopus oocytes as a model system, we investigated the possible involvement of ras proteins in the pathway leading to phosphorylation of ribosomal protein S6. Our results indicate that microinjection of oncogenic T24 H-ras protein (which contains valine at position 12) markedly stimulated S6 phosphorylation on serine residues in oocytes, whereas normal ras protein (which contains glycine at position 12) was without effect. The S6 phosphorylation activity in the cell extract from T24 ras protein-injected oocytes was increased significantly. In addition, injection of protein kinase C potentiated the induction of maturation and S6 phosphorylation by the oncogenic ras protein. A similar potentiation was detected when T24 ras protein-injected oocytes were incubated with active phorbol ester. These findings suggest that ras proteins activate the pathway linked to S6 phosphorylation and that protein kinase C has a synergistic effect on the ras-mediated pathway.

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Kamata, T., and H. F. Kung. "Modulation of maturation and ribosomal protein S6 phosphorylation in Xenopus oocytes by microinjection of oncogenic ras protein and protein kinase C." Molecular and Cellular Biology 10, no. 3 (March 1990): 880–86. http://dx.doi.org/10.1128/mcb.10.3.880.

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Using Xenopus oocytes as a model system, we investigated the possible involvement of ras proteins in the pathway leading to phosphorylation of ribosomal protein S6. Our results indicate that microinjection of oncogenic T24 H-ras protein (which contains valine at position 12) markedly stimulated S6 phosphorylation on serine residues in oocytes, whereas normal ras protein (which contains glycine at position 12) was without effect. The S6 phosphorylation activity in the cell extract from T24 ras protein-injected oocytes was increased significantly. In addition, injection of protein kinase C potentiated the induction of maturation and S6 phosphorylation by the oncogenic ras protein. A similar potentiation was detected when T24 ras protein-injected oocytes were incubated with active phorbol ester. These findings suggest that ras proteins activate the pathway linked to S6 phosphorylation and that protein kinase C has a synergistic effect on the ras-mediated pathway.

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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.

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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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Guadagni, Stefano, Antonietta Rosella Farina, Lucia Annamaria Cappabianca, Michela Sebastiano, Rita Maccarone, Veronica Zelli, Marco Clementi, et al. "Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6–7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A." International Journal of Molecular Sciences 21, no. 21 (November 3, 2020): 8222. http://dx.doi.org/10.3390/ijms21218222.

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Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6–7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L’Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6–7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6–7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6–7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6–7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6–7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.

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Stacey, Dennis W., Masahiro Hitomi, and Guan Chen. "Influence of Cell Cycle and Oncogene Activity upon Topoisomerase IIα Expression and Drug Toxicity." Molecular and Cellular Biology 20, no. 24 (December 15, 2000): 9127–37. http://dx.doi.org/10.1128/mcb.20.24.9127-9137.2000.

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ABSTRACT The cell cycle, oncogenic signaling, and topoisomerase (topo) IIα levels all influence sensitivity to anti-topo II drugs. Because the cell cycle and oncogenic signaling influence each other as well as topo IIα levels, it is difficult to assess the importance of any one of these factors independently of the others during drug treatment. Such information, however, is vital to an understanding of the cellular basis of drug toxicity. We, therefore, developed a series of analytical procedures to individually assess the role of each of these factors during treatment with the anti-topo II drug etoposide. All studies were performed with asynchronously proliferating cultures by the use of time-lapse and quantitative fluorescence staining procedures. To our surprise, we found that neither oncogene action nor the cell cycle altered topo IIα protein levels in actively cycling cells. Only a minor population of slowly cycling cells within these cultures responded to constitutively active oncogenes by elevating topo IIα production. Thus, it was possible to study the effects of the cell cycle and oncogene action on drug-treated cells while topo IIα levels remained constant. Toxicity analyses were performed with two consecutive time-lapse observations separated by a brief drug treatment. The cell cycle phase was determined from the first observation, and cell fate was determined from the second. Cells were most sensitive to drug treatment from mid-S phase through G2 phase, with G1 phase cells nearly threefold less sensitive. In addition, the presence of an oncogenicsrc gene or microinjected Ras protein increased drug toxicity by approximately threefold in actively cycling cells and by at least this level in the small population of slowly cycling cells. We conclude that both cell cycle phase and oncogenic signaling influence drug toxicity independently of alterations in topo IIα levels.

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Walentynowicz, Kacper, Dalit Engelhardt, Shreya Yadav, Ugoma Onubogu, Roberto Salatino, Cristina Vincentelli, Thomas McDonald, Franziska Michor, and Michalina Janiszewska. "PATH-29. GLIOBLASTOMA TUMOR CLASSIFICATION BASED ON SPATIAL ANALYSIS OF ONCOGENIC AMPLIFICATIONS AND PROTEIN EXPRESSION." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi121. http://dx.doi.org/10.1093/neuonc/noab196.481.

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Abstract Heterogeneity of glioblastoma (GBM) has been extensively studied in recent years with identification of oncogenic drivers of GBM cellular subtypes. However, little is known about how these cells interact with each other or with the surrounding tumor microenvironment (TME). We employed spatial protein profiling targeting immune and neuronal markers (79 proteins) coupled with single-cell spatial maps of fluorescence in situ hybridization (FISH) for EGFR, CDK4, and PDGFRA on human GBM tissue sections. Several cores from 20 GBM samples were collected to create a tissue microarray, and 96 regions of interests were profiled with 37,844 nuclei for oncogenic amplification screen. Spatial protein profiling identified strong correlation of certain immune markers, TAU-associated proteins, and oligodendrocyte-enriched protein groups and overall high intratumor heterogeneity of TME. Our single-cell quantification of FISH signals showed differences among tumors based on the prevalence of dual amplification of EGFR and CDK4 within a cell relative to single oncogene amplified cells. High relative frequency of dual amplification was associated with increased expression of immune-related markers and decreased expression of EGFR protein. Moreover, this protein expression signature was associated with survival in another GBM dataset. Here, we present spatial genetic analysis at the single cell level coupled with protein expression profiles associated with tumor microenvironment. Our results suggest that assessment of genetic heterogeneity in GBM could potentially drive improved patient stratification and treatment.

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Pomerance, M., M. N. Thang, B. Tocque, and M. Pierre. "The Ras-GTPase-activating protein SH3 domain is required for Cdc2 activation and mos induction by oncogenic Ras in Xenopus oocytes independently of mitogen-activated protein kinase activation." Molecular and Cellular Biology 16, no. 6 (June 1996): 3179–86. http://dx.doi.org/10.1128/mcb.16.6.3179.

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The Ras-GTPase-activating protein (RasGAP) is an important modulator of p21ras - dependent signal transduction in Xenopus oocytes and in mammalian cells. We investigated the role of the RasGAP SH3 domain in signal transduction with a monoclonal antibody against the SH3 domain of RasGaP. This antibody prevented the activation of the maturation-promoting factor complex (cyclin B-p34cdc2) by oncogenic Ras. The antibody appears to be specific because as little as 5 ng injected per oocyte reduced the level of Cdc2 activation by 50% whereas 100 ng of nonspecific immunoglobulin G did not affect Cdc2 activation. The antibody blocked the Cdc2 activation induced by oncogenic Ras but not that induced by progesterone, which acts independently of Ras. A peptide corresponding to positions 317 to 326 of a sequence in the SH3 domain of human RasGAP blocked Cdc2 activation, whereas a peptide corresponding to positions 273 to 305 of a sequence in the N-terminal moiety of the SH3 domain of RasGAP had no effect. The antibody did not block the mitogen-activated protein (MAP) kinase cascade (activation of MAPK/ERK kinase [MEK], MAP kinase, and S6 kinase p90rsk). Surprisingly, injection of the negative MAP kinase mutant protein ERK2 K52R (containing a K-to-R mutation at position 52) blocked the Cdc2 activation induced by oncogenic Ras as well as blocking the activation of MAP kinase. Thus, MAP kinase is also implicated in the regulation of Cdc2 activity. In this study, we further investigated the regulation of the synthesis of the c-mos oncogene product, which is necessary for the activation of Cdc2. We report that the synthesis of the c-mos oncogene product, which is necessary for the activation antibody to the SH3 domain of RasGAP and by injecting the negative MAP kinase mutant protein ERK2 K52R. These results suggest that oncogenic Ras activates two signaling mechanisms: the MAP kinase cascade and a signaling pathway implicating the SH3 domain of RasGAP. These mechanisms might control Mos protein expression implicated in Cdc2 activation.

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Qi, Qi, Dean Y. Li, Hongbo R. Luo, Kun-Liang Guan, and Keqiang Ye. "Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability." Proceedings of the National Academy of Sciences 112, no. 23 (May 26, 2015): 7255–60. http://dx.doi.org/10.1073/pnas.1505917112.

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Yes-associated protein (YAP), a transcription coactivator, is the major downstream effector of the Hippo pathway, which plays a critical role in organ size control and cancer development. However, how YAP is regulated by extracellular stimuli in tumorigenesis remains incompletely understood. Netrin-1, a laminin-related secreted protein, displays proto-oncogenic activity in cancers. Nonetheless, the downstream signaling mediating its oncogenic effects is not well defined. Here we show that netrin-1 via its transmembrane receptors, deleted in colorectal cancer and uncoordinated-5 homolog, up-regulates YAP expression, escalating YAP levels in the nucleus and promoting cancer cell proliferation and migration. Inactivating netrin-1, deleted in colorectal cancer, or uncoordinated-5 homolog B (UNC5B) decreases YAP protein levels, abrogating cancer cell progression by netrin-1, whereas knockdown of mammalian STE20-like protein kinase 1/2 (MST1/2) or large tumor suppressor kinase 1/2 (Lats1/2), two sets of upstream core kinases of the Hippo pathway, has no effect in blocking netrin-1–induced up-regulation of YAP. Netrin-1 stimulates phosphatase 1A to dephosphorylate YAP, which leads to decreased ubiquitination and degradation, enhancing YAP accumulation and signaling. Hence, our findings support that netrin-1 exerts oncogenic activity through YAP signaling, providing a mechanism coupling extracellular signals to the nuclear YAP oncogene.

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Chang, Jun, Se-Hwan Yang, Young-Gyu Cho, Soon Bong Hwang, Young Shin Hahn, and Young Chul Sung. "Hepatitis C Virus Core from Two Different Genotypes Has an Oncogenic Potential but Is Not Sufficient for Transforming Primary Rat Embryo Fibroblasts in Cooperation with the H-ras Oncogene." Journal of Virology 72, no. 4 (April 1, 1998): 3060–65. http://dx.doi.org/10.1128/jvi.72.4.3060-3065.1998.

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ABSTRACT Persistent infection with hepatitis C virus (HCV) is associated with the development of liver cirrhosis and hepatocellular carcinoma. To examine the oncogenic potential of the HCV core gene product, primary rat embryo fibroblasts (REFs) were transfected with the core gene in the presence or absence of the H-ras oncogene. In contrast to a previous report (R. B. Ray, L. M. Lagging, K. Meyer, and R. Ray, J. Virol. 70:4438–4443, 1996), HCV core proteins from two different genotypes (type 1a and type 1b) were not found to transform REFs to tumorigenic phenotype in cooperation with the H-ras oncogene, although the core protein was successfully expressed 20 days after transfection. In addition, REFs transfected with E1A- but not core-expressing plasmid showed the phenotype of immortalized cells when selected with G418. The biological activity was confirmed by observing the transcription activation from two viral promoters, Rous sarcoma virus long terminal repeat and simian virus 40 promoter, which are known to be activated by the core protein from HCV-1 isolate. In contrast to the result with primary cells, the Rat-1 cell line, stably expressing HCV core protein, exhibited focus formation, anchorage-independent growth, and tumor formation in nude mice. HCV core protein was able to induce the transformation of Rat-1 cells with various efficiencies depending on the expression level of the core protein. These results indicate that HCV core protein has an oncogenic potential to transform the Rat-1 cell line but is not sufficient to either immortalize primary REFs by itself or transform primary cells in conjunction with the H-ras oncogene.

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Satoh, T., S. Nakamura, and Y. Kaziro. "Induction of neurite formation in PC12 cells by microinjection of proto-oncogenic Ha-ras protein preincubated with guanosine-5'-O-(3-thiotriphosphate)." Molecular and Cellular Biology 7, no. 12 (December 1987): 4553–56. http://dx.doi.org/10.1128/mcb.7.12.4553-4556.1987.

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Rat pheochromocytoma (PC12) cells differentiate to neuronal cells in response to nerve growth factor. It has been shown that microinjection of oncogenic but not proto-oncogenic p21 protein induces morphological differentiation in PC12 cells (D. Bar-Sagi and J. R. Feramisco, Cell 42:841-848, 1985). In this paper we describe a recombinant human proto-oncogenic Ha-ras protein which can effectively induce neurite extension of PC12 cells when microinjected as a complex with guanosine-5'-O-(3-thiotriphosphate). The protein was found to be less effective when complexed with GTP. On the other hand, an oncogenic ras protein coinjected with guanosine-5'-O-(2-thiodiphosphate) was entirely inactive. These results indicate that the binary p21-GTP complex, but not the p21-GDP complex, is effective in inducing differentiation in PC12 cells, irrespective of the oncogenic or the proto-oncogenic protein.

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Satoh, T., S. Nakamura, and Y. Kaziro. "Induction of neurite formation in PC12 cells by microinjection of proto-oncogenic Ha-ras protein preincubated with guanosine-5'-O-(3-thiotriphosphate)." Molecular and Cellular Biology 7, no. 12 (December 1987): 4553–56. http://dx.doi.org/10.1128/mcb.7.12.4553.

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Rat pheochromocytoma (PC12) cells differentiate to neuronal cells in response to nerve growth factor. It has been shown that microinjection of oncogenic but not proto-oncogenic p21 protein induces morphological differentiation in PC12 cells (D. Bar-Sagi and J. R. Feramisco, Cell 42:841-848, 1985). In this paper we describe a recombinant human proto-oncogenic Ha-ras protein which can effectively induce neurite extension of PC12 cells when microinjected as a complex with guanosine-5'-O-(3-thiotriphosphate). The protein was found to be less effective when complexed with GTP. On the other hand, an oncogenic ras protein coinjected with guanosine-5'-O-(2-thiodiphosphate) was entirely inactive. These results indicate that the binary p21-GTP complex, but not the p21-GDP complex, is effective in inducing differentiation in PC12 cells, irrespective of the oncogenic or the proto-oncogenic protein.

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Piastra, Valentina, Angelina Pranteda, and Gianluca Bossi. "Dissection of the MKK3 Functions in Human Cancer: A Double-Edged Sword?" Cancers 14, no. 3 (January 18, 2022): 483. http://dx.doi.org/10.3390/cancers14030483.

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The role played by MKK3 in human cancer is controversial. MKK3 is an evolutionarily conserved protein kinase that activates in response to a variety of stimuli. Phosphorylates, specifically the p38MAPK family proteins, contribute to the regulation of a plethora of cellular processes such as proliferation, differentiation, apoptosis, invasion, and cell migration. Genes in carcinogenesis are classified as oncogenes and tumor suppressors; however, a clear distinction is not always easily made as it depends on the cell context and tissue specificity. The aim of this study is the examination of the potential contribution of MKK3 in cancer through a systematic analysis of the recent literature. The overall results reveal a complex scenario of MKK3′s involvement in cancer. The oncogenic functions of MKK3 were univocally documented in several solid tumors, such as colorectal, prostate cancer, and melanoma, while its tumor-suppressing functions were described in glioblastoma and gastric cancer. Furthermore, a dual role of MKK3 as an oncogene as well as tumor a suppressor has been described in breast, cervical, ovarian, liver, esophageal, and lung cancer. However, overall, more evidence points to its role as an oncogene in these diseases. This review indicates that the oncogenic and tumor-suppressing roles of MKK3 are strictly dependent on the tumor type and further suggests that MKK3 could represent an efficient putative molecular target that requires contextualization within a specific tumor type in order to adequately evaluate its potential effectiveness in designing novel anticancer therapies.

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Cupic, Maja, Ivana Lazarevic, and Nada Kuljic-Kapulica. "Oncogenic viruses and their role in tumor formation." Srpski arhiv za celokupno lekarstvo 133, no. 7-8 (2005): 384–87. http://dx.doi.org/10.2298/sarh0508384c.

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Oncogenic viruses trigger persistent infections, which can stimulate uncontrolled cell growth by inducing cell transformation. Different oncogenic viruses use different mechanisms for infecting cells. Most oncogenic DNA viruses integrate transforming sets of genes into the host chromosome and encode proteins that bind and inactivate cell growth regulatory proteins, such as p53 and retinoblastoma gene product. Tumorous RNA viruses use different oncogenic mechanisms. Some of them encode oncogenic proteins that are almost identical to the cellular proteins involved in the control of cellular growth. The overproduction or altered function of these oncogenic materials stimulates cell growth. These RNA viruses can cause tumors rapidly. The second group of oncoviruses integrates their promoter sequences and viral enhancers near to the cellular growth-stimulating gene, initiating the transformation of the cell. The third group of RNA tumor viruses encodes a protein tax that transactivates the expression of cellular genes. Virus-induced malignant transformation of the cell represents the first step in the complex process of oncogenesis.

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Kaida, Atsushi, and Tomoo Iwakuma. "Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members." International Journal of Molecular Sciences 22, no. 24 (December 16, 2021): 13527. http://dx.doi.org/10.3390/ijms222413527.

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Heat shock proteins (HSPs) are molecular chaperones that assist diverse cellular activities including protein folding, intracellular transportation, assembly or disassembly of protein complexes, and stabilization or degradation of misfolded or aggregated proteins. HSP40, also known as J-domain proteins (JDPs), is the largest family with over fifty members and contains highly conserved J domains responsible for binding to HSP70 and stimulation of the ATPase activity as a co-chaperone. Tumor suppressor p53 (p53), the most frequently mutated gene in human cancers, is one of the proteins that functionally interact with HSP40/JDPs. The majority of p53 mutations are missense mutations, resulting in acquirement of unexpected oncogenic activities, referred to as gain of function (GOF), in addition to loss of the tumor suppressive function. Moreover, stability and levels of wild-type p53 (wtp53) and mutant p53 (mutp53) are crucial for their tumor suppressive and oncogenic activities, respectively. However, the regulatory mechanisms of wtp53 and mutp53 are not fully understood. Accumulating reports demonstrate regulation of wtp53 and mutp53 levels and/or activities by HSP40/JDPs. Here, we summarize updated knowledge related to the link of HSP40/JDPs with p53 and cancer signaling to improve our understanding of the regulation of tumor suppressive wtp53 and oncogenic mutp53 GOF activities.

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Lacal, J. C., A. Cuadrado, J. E. Jones, R. Trotta, D. E. Burstein, T. Thomson, and A. Pellicer. "Regulation of protein kinase C activity in neuronal differentiation induced by the N-ras oncogene in PC-12 cells." Molecular and Cellular Biology 10, no. 6 (June 1990): 2983–90. http://dx.doi.org/10.1128/mcb.10.6.2983-2990.1990.

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Abstract:

Expression of the N-ras oncogene under the control of the glucocorticoid-responsive promoter in the pheochromocytoma cell line UR61, a subline of PC-12 cells, has been used to investigate the differentiation process to neuronal cells triggered by ras oncogenes (I. Guerrero, A. Pellicer, and D. E. Burstein, Biochem. Biophys. Res. Commun. 150:1185-1192, 1988). Using ras-inducible cell lines, we observed that expression of the oncogenic N-ras p21 protein interferes with the ability of phorbol esters to induce downregulation of protein kinase C. This effect was associated with the appearance of immunologically detectable protein kinase C as well as the activity of the enzyme as analyzed either by binding of [3H]phorbol-12,13-dibutyrate in intact cells or by in vitro kinase activity. These results indicate a relationship between ras p21 and protein kinase C in neuronal differentiation in this model system. Comparison to the murine fibroblast system suggests that this relationship may be functional.

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Journal articles on the topic 'Oncogenic protein'

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