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Journal articles on the topic 'Growth-regulated oncogene'

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Published: 10 December 2022
Last updated: 28 January 2023

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1

Chernov, A. N. "The impact of the nerve growth factor on the number of MYCC, MYCN oncogene copies in human medulloblastoma cells." Malignant tumours 9, no. 1 (April 10, 2019): 22–28. http://dx.doi.org/10.18027/2224-5057-2019-9-1-22-28.

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Introduction: The search for new molecular targets for chemotherapy of malignancies, particularly pediatric brain tumors, is a relevant issue of modern oncology. MYC expression and amplification is often observed in brain tumors, which is an unfavorable prognostic factor. Many oncogenic processes are regulated by some growth factors including the nerve growth factor (NGF).Purpose: To study the changes in the number of MYCCand MYCN‑gene copies in MB cells exposed to the NGF.Material and methods: The impact of the NGF on the number of MYCC‑, MYCN oncogene copies in the primary human medulloblastoma cell culture was assessed using the method of fluorescence in situ hybridization.Results: Exposure to the NGF was shown to decrease the number of MB cells containing 6, 8 copies of MYCN oncogenes and 3, 8 copies of MYCC oncogene. The NGF was also shown to increase the number of tumor cells that contain a double set of copies of both oncogenes. There was a statistically significant (p<0.0001) negative correlation (r=–0.65) between the average number of MYCC oncogene copies and the NGF cytotoxicity index.Conclusion: The increased number of oncogene copies reduces the susceptibility of MB cells to the growth factor.
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2

Karpatkin, Simon. "Growth regulated oncogene is pivotal in thrombin-induced angiogenesis." Thrombosis Research 120 (January 2007): S71—S74. http://dx.doi.org/10.1016/s0049-3848(07)70133-0.

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3

Caunt, Maresa, Liang Hu, Thomas Tang, Peter C. Brooks, Sherif Ibrahim, and Simon Karpatkin. "Growth-Regulated Oncogene Is Pivotal in Thrombin-Induced Angiogenesis." Cancer Research 66, no. 8 (April 15, 2006): 4125–32. http://dx.doi.org/10.1158/0008-5472.can-05-2570.

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4

Lee, Wei-Ping, Yong Liao, Dan Robinson, Hsing-Jien Kung, Edison T. Liu, and Mien-Chie Hung. "Axl-Gas6 Interaction Counteracts E1A-Mediated Cell Growth Suppression and Proapoptotic Activity." Molecular and Cellular Biology 19, no. 12 (December 1, 1999): 8075–82. http://dx.doi.org/10.1128/mcb.19.12.8075.

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ABSTRACT The adenovirus type 5 early region 1A gene (E1A) has previously been known as an immortalization oncogene because E1A is required for transforming oncogenes, such as ras andE1B, to transform cells in primary cultures. However, E1A has also been shown to downregulate the overexpression of theHer-2/neu oncogene, resulting in suppression of transformation and tumorigenesis induced by that oncogene. In addition, E1A is able to promote apoptosis induced by anticancer drugs, irradiation, and serum deprivation. Many tyrosine kinases, such as the epidermal growth factor receptor, Her-2/Neu, Src, and Axl, are known to play a role in oncogenic signals in transformed cells. To study the mechanism underlying the E1A-mediated tumor-suppressing function, we exploited a modified tyrosine kinase profile assay (D. Robinson, F. Lee, T. Pretlow, and H.-J. Kung, Proc. Natl. Acad. Sci. USA 93:5958–5962, 1996) to identify potential tyrosine kinases regulated by E1A. Reverse transcription (RT)-PCR products were synthesized with two degenerate primers derived from the conserved motifs of various tyrosine kinases. A tyrosine kinase downregulated by E1A was identified by analyzing the AluI-digested RT-PCR products. We isolated the DNA fragment of interest and found that E1A negatively regulated the expression of the transforming receptor tyrosine kinase Axl at the transcriptional level. To study whether downregulation of the Axl receptor is involved in E1A-mediated growth suppression, we transfectedaxl cDNA into E1A-expressing cells (ip1-E1A) to establish cells that overexpressed Axl. The Axl ligand Gas6 triggered a greater mitogenic effect in these ip1-E1A-Axl cells than in ip1-E1A control cells and protected the Axl-expressing cells from serum deprivation-induced apoptosis. These results indicate that downregulation of the Axl receptor by E1A is involved in E1A-mediated growth suppression and E1A-induced apoptosis and thereby contributes to E1A’s antitumor activities.
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Zhang, Xin, Tao Zhu, Yong Chen, Hichem C. Mertani, Kok-Onn Lee, and Peter E. Lobie. "Human Growth Hormone-regulated HOXA1 Is a Human Mammary Epithelial Oncogene." Journal of Biological Chemistry 278, no. 9 (December 13, 2002): 7580–90. http://dx.doi.org/10.1074/jbc.m212050200.

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6

Caunt, Maresa, Liang Hu, Thomas Tang, Peter C. Brooks, and Simon Karpatkin. "Growth Regulated Oncogene (GRO-α) Is Pivotal in Thrombin-Induced Angiogenesis." Blood 106, no. 11 (November 16, 2005): 530. http://dx.doi.org/10.1182/blood.v106.11.530.530.

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Abstract The mechanism of thrombin-induced angiogenesis is poorly understood. Using a gene chip array to investigate the pro-malignant phenotype of thrombin-stimulated cells we observed that thrombin (0.5–1 u/ml/24 hr) upregulates GRO-α 168 fold in an undifferentiated mouse cell line (UMCL). Thrombin-induced GRO-α upregulation was also observed in several tumor cell lines [murine B16F10 melanoma and 4T1 breast CA, human DU145 and PC3 prostate CA, human MCF7 breast CA, as well as human umbilical vein (HUVEC) and brain microvascular endothelial cells] by mRNA and protein analysis. Thrombin enhanced the secretion of GRO-α from PC3 and MCF7 cells 25–64 fold at 24 hrs. GRO-α is a CXC chemokine oncogene that binds to a seven transmembrane receptor, CXCR2 and enhances growth, chemotaxis and metastasis of several tumor cell lines. GRO-α induced metastasis is associated with increased angiogenesis. To obtain a better understanding of neoangiogenesis mechanisms involved in the thrombin-stimulated malignant phenotype we examined the effect of anti-GRO-α Ab on thrombin-induced angiogenesis in the CAM assay at 72 hrs. GRO-α (5ug/egg/day) enhanced angiogenesis 2.2 fold (n=19, p=0.005), providing direct evidence for GRO-α as an angiogenic growth factor. Thrombin also enhanced angiogenesis 2.7 fold (n=9, p=0.01), however, anti-GRO-α Ab inhibited thrombin-induced angiogenesis to basal control levels whereas IgG control Ab had no effect (n=9). Similar results were obtained with an endothelial (HUVEC) cord formation assay in matrigel. Thrombin-induced cord formation increased 1.5 fold (n=20, p<0.0001) at 24 hrs which was inhibited by anti-GRO-α Ab to basal control levels (n=6, p<0.01). We next examined the relationship between thrombin and GRO-α on the upregulation of various vascular growth factors and receptor genes in HUVEC at 24 hrs. Thrombin as well as its PAR-1 receptor activation peptide (TRAP, 100 uM) as well as GRO-α (3 ug/ml) all markedly upregulated (>2-4 fold) KDR, Ang-2, MMP-1, MMP-2, CXCR2 and CD31 (angiogenesis marker) protein compared to control cells (n=3). Similar upregulation of GRO-α was also noted in tumor cells (PC3, B16F10 and 4T1 cells) (n=3). All of the thrombin/TRAP gene upregulations were completely inhibited by anti-GRO-α Ab and unaffected by irrelevant Ab-treated cells (n=3). bFGF and VEGF had no effect on upregulation of GRO-α (immunoblot) yet they upregulated other vascular growth factors, demonstrating specificity for thrombin. Similar inhibition of thrombin upregulation of vascular growth factors was noted in siRNA GRO-α knock down (KD) HUVEC as well as 4T1 and B16F10 cells. In vivo tumor growth studies in wild-type mice injected with subcutaneous GRO-α KD 4T1 cells revealed 2-4 fold impaired tumor growth, spontaneous metastasis and angiogenesis which was not affected by endogenous thrombin (hirudin treatment). Thus thrombin-induced angiogenesis requires the upregulation of GRO-α. Thrombin upregulation of GRO-α in tumor cells as well as endothelial cells, contributes to tumor angiogenesis.
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7

Nandi, Sisir, and Manish C. Bagchi. "Exploring CDKs, Ras-ERK, and PI3K-Aktin Abnormal Signaling and Cancer." Journal of Cancer Research Updates 11 (October 27, 2022): 63–69. http://dx.doi.org/10.30683/1929-2279.2022.11.09.

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Cancer or malignancy can be defined as abnormal growth and cell division. Malignancies spread, through metastasis invasion, or implantation into distant sites by which cancer cells can move through the bloodstream or lymphatic system to distant locations. The body cells follow mitotic cell division process. Normal cell division occurs through the normal signal transduction through proto-oncogenes responsible for the cell proliferation and differentiation. Mutation of these proto-oncogene leads to oncogene which can modify the gene expression and function through abnormal signal transduction, making uncontrolled growth of cells. The mitotic cell cycle is regulated by the signal transduction through the cyclin dependent kinases (CDKs), Ras-ERK and PI3K-Akt.Abnormal signaling occurs through the mutation of these genes leading to the cancer. The present review shortly reported the role of these proteins in abnormal signal transduction and cancer.
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8

Robinson, Shenandoah, Marie Tani, Robert M. Strieter, Richard M. Ransohoff, and Robert H. Miller. "The Chemokine Growth-Regulated Oncogene-α Promotes Spinal Cord Oligodendrocyte Precursor Proliferation." Journal of Neuroscience 18, no. 24 (December 15, 1998): 10457–63. http://dx.doi.org/10.1523/jneurosci.18-24-10457.1998.

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9

Lane, Brian R., Jianguo Liu, Paul J. Bock, Dominique Schols, Michael J. Coffey, Robert M. Strieter, Peter J. Polverini, and David M. Markovitz. "Interleukin-8 and Growth-Regulated Oncogene Alpha Mediate Angiogenesis in Kaposi's Sarcoma." Journal of Virology 76, no. 22 (November 15, 2002): 11570–83. http://dx.doi.org/10.1128/jvi.76.22.11570-11583.2002.

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ABSTRACT The development of the complex neoplasm Kaposi's sarcoma is dependent on infection with the Kaposi's sarcoma-associated herpesvirus (KSHV) and appears to be greatly enhanced by cytokines and human immunodeficiency virus type 1 (HIV-1) Tat. Interleukin-8 (IL-8) and growth-regulated oncogene alpha (GRO-α) are chemokines involved in chemoattraction, neovascularization, and stimulation of HIV-1 replication. We have previously demonstrated that production of GRO-α is stimulated by exposure of monocyte-derived macrophages (MDM) to HIV-1. Here we show that exposure of MDM to HIV-1, viral Tat, or viral gp120 leads to a substantial increase in IL-8 production. We also demonstrate that IL-8 and GRO-α are induced by KSHV infection of endothelial cells and are crucial to the angiogenic phenotype developed by KSHV-infected endothelial cells in cell culture and upon implantation into SCID mice. Thus, the three known etiological factors in Kaposi's sarcoma pathogenesis—KSHV, HIV-1 Tat, and cellular growth factors—might be linked, in part, through induction of IL-8 and GRO-α.
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10

Nasu, K. "Expression and regulation of growth-regulated oncogene alpha in human endometrial stromal cells." Molecular Human Reproduction 7, no. 8 (August 1, 2001): 741–46. http://dx.doi.org/10.1093/molehr/7.8.741.

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11

Jung, Jae-Joon, Sewon Noh, Hei-Cheul Jeung, Minkyu Jung, Tae Soo Kim, Sung Hoon Noh, Jae Kyung Roh, Hyun Cheol Chung, and Sun Young Rha. "Chemokine growth-regulated oncogene 1 as a putative biomarker for gastric cancer progression." Cancer Science 101, no. 10 (August 22, 2010): 2200–2206. http://dx.doi.org/10.1111/j.1349-7006.2010.01666.x.

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12

Teichler, Sabine, Thomas Illmer, Josephine Roemhild, Dmitriy Ovcharenko, Thorsten Stiewe, and Andreas Neubauer. "MicroRNA29a regulates the expression of the nuclear oncogene Ski." Blood 118, no. 7 (August 18, 2011): 1899–902. http://dx.doi.org/10.1182/blood-2010-09-306258.

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Abstract MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate growth and differentiation. miRNAs are frequently located at cancer-specific fragile sites in the human genome, such as chromosome 7q. The nuclear oncogene SKI is up-regulated in acute myeloid leukemia (AML) with −7/del7q. Here we asked whether loss of miRNAs on chromosome 7q may explain this up-regulation. miR-29a expression was found to be down-regulated in AML with −7/del7q. Forced expression of miR-29a down-regulated Ski and its target gene, Nr-CAM, whereas miR-29a inhibition induced Ski expression. Luciferase assays validated a functional binding site for miR-29a in the 3′ untranslated region of SKI. Finally, in samples of AML patients, we observed an inverse correlation of Ski and miR-29a expression, respectively. In conclusion, up-regulation of Ski in AML with −7/del7q is caused by loss of miR-29a. miR-29a may therefore function as an important tumor suppressor in AML by restraining expression of the SKI oncogene.
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13

Yang, Tony, Cayla Boycott, Katarzyna Lubecka, and Barbara Stefanska. "BRUNOL5 as a Novel Oncogene Is Epigenetically Regulated by Stilbenoids in Primary Liver Cancer Cells." Current Developments in Nutrition 5, Supplement_2 (June 2021): 287. http://dx.doi.org/10.1093/cdn/nzab036_029.

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Abstract Objectives We previously discovered that a novel gene, BRUNOL5, is hypomethylated at the promoter region and upregulated in patients with primary liver cancer. Since DNA hypomethylation was shown to underlie up-regulation of genes with oncogenic functions, BRUNOL5 could potentially act as an oncogene. Interestingly, certain dietary compounds such as polyphenols with a stilbenoid ring have been demonstrated by us and others to suppress hypomethylated cancer-driving genes. In the present study, we investigate BRUNOL5 oncogenic functions and the role of two stilbenoids, resveratrol (RSV) and pterostilbene (PTS), in BRUNOL5 transcriptional regulation. Methods Liver cancer cells, HepG2 and SkHep1, were treated with 15µM RSV or 10µM PTS for 9 days followed by the analysis of cell growth (trypan blue exclusion test), anchorage-independent growth (soft-agar assay), and invasiveness (Boyden chamber assay). The effect on BRUNOL5 promoter methylation and gene expression was assessed by pyrosequencing and QPCR, respectively. BRUNOL5 was then depleted in HepG2 cells using siRNA followed by RNA sequencing to establish gene expression profiles. Results BRUNOL5 was down-regulated by 95% in response to RSV and by 25–50% in response to PTS. This coincided with 10–15% hypermethylation of BRUNOL5 promoter. This effect on BRUNOL5 transcriptional regulation was associated with robust decrease in cell growth, anchorage independent growth and invasiveness. Interestingly, depletion of BRUNOL5 in HepG2 cells mimicked polyphenols’ anti-cancer effects. Further investigation by RNA sequencing in BRUNOL5-depleted cells established gene targets potentially regulated by BRUNOL5. We found 4,406 genes significantly differentially expressed in response to BRUNOL5 knockdown. The top downregulated genes included cancer-promoting genes such as FAIM2, AMOTL1, and MMP2; whereas tumor suppressor genes such as MT1G, CADH1, and ALDH1L1 were among genes with the highest upregulation. Conclusions Our findings demonstrate that BRUNOL5 is a novel target of stilbenoids and acts as an oncogene in liver cancer. RSV and PTS may exert their anti-cancer effects, at least partially, through BRUNOL5 downregulation. Funding Sources UBC VP Academic Award, CFI John. R. Evans Leaders Fund, and BC Knowledge Development Fund granted to BS
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14

Leung, Wai-Hung, Jing-Wen Shih, Jian-Syun Chen, Ntlotlang Mokgautsi, Po-Li Wei, and Yan-Jiun Huang. "Preclinical Identification of Sulfasalazine’s Therapeutic Potential for Suppressing Colorectal Cancer Stemness and Metastasis through Targeting KRAS/MMP7/CD44 Signaling." Biomedicines 10, no. 2 (February 4, 2022): 377. http://dx.doi.org/10.3390/biomedicines10020377.

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Approximately 25% of colorectal cancer (CRC) patients will develop metastatic (m)CRC despite treatment interventions. In this setting, tumor cells are attracted to the epidermal growth factor receptor (EGFR) oncogene. Kirsten rat sarcoma (RAS) 2 viral oncogene homolog (KRAS) mutations were reported to drive CRC by promoting cancer progression in activating Wnt/β-catenin and RAS/extracellular signal-regulated kinase (ERK) pathways. In addition, KRAS is associated with almost 40% of patients who acquire resistance to EGFR inhibitors in mCRC. Multiple studies have demonstrated that cancer stem cells (CSCs) promote tumorigenesis, tumor growth, and resistance to therapy. One of the most common CSC prognostic markers widely reported in CRC is a cluster of differentiation 44 (CD44), which regulates matrix metalloproteinases 7/9 (MMP7/9) to promote tumor progression and metastasis; however, the molecular role of CD44 in CRC is still unclear. In invasive CRC, overexpression of MMP7 was reported in tumor cells compared to normal cells and plays a crucial function in CRC cetuximab and oxaliplatin resistance and distant metastasis. Here, we utilized a bioinformatics analysis and identified overexpression of KRAS/MMP7/CD44 oncogenic signatures in CRC tumor tissues compared to normal tissues. In addition, a high incidence of mutations in KRAS and CD44 were associated with some of the top tumorigenic oncogene’s overexpression, which ultimately promoted a poor response to chemotherapy and resistance to some FDA-approved drugs. Based on these findings, we explored a computational approach to drug repurposing of the drug, sulfasalazine, and our in silico molecular docking revealed unique interactions of sulfasalazine with the KRAS/MMP7/CD44 oncogenes, resulting in high binding affinities compared to those of standard inhibitors. Our in vitro analysis demonstrated that sulfasalazine combined with cisplatin reduced cell viability, colony, and sphere formation in CRC cell lines. In addition, sulfasalazine alone and combined with cisplatin suppressed the expression of KRAS/MMP7/CD44 in DLD-1 and HCT116 cell lines. Thus, sulfasalazine is worthy of further investigation as an adjuvant agent for improving chemotherapeutic responses in CRC patients.
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15

Lee, Zendra, Ramona F. Swaby, Yuewei Liang, Shuangxing Yu, Shuying Liu, Karen H. Lu, Robert C. Bast, Gordon B. Mills, and Xianjun Fang. "Lysophosphatidic Acid Is a Major Regulator of Growth-Regulated Oncogene α in Ovarian Cancer." Cancer Research 66, no. 5 (March 1, 2006): 2740–48. http://dx.doi.org/10.1158/0008-5472.can-05-2947.

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16

Hofer, Livia S., Sara Mariotto, Sebastian Wurth, Sergio Ferrari, Chiara R. Mancinelli, Rachele Delogu, Salvatore Monaco, et al. "Distinct serum and cerebrospinal fluid cytokine and chemokine profiles in autoantibody-associated demyelinating diseases." Multiple Sclerosis Journal - Experimental, Translational and Clinical 5, no. 2 (April 2019): 205521731984846. http://dx.doi.org/10.1177/2055217319848463.

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Background Demyelinating diseases of the central nervous system associated with autoantibodies against aquaporin-4 and myelin-oligodendrocyte-glycoprotein are mediated by different immunopathological mechanisms compared to multiple sclerosis. Objective The purpose of this study was to evaluate serum and cerebrospinal fluid cytokine/chemokine profiles in patients with autoantibodies against aquaporin-4 or autoantibodies against myelin-oligodendrocyte-glycoprotein-associated demyelination compared to multiple sclerosis and autoimmune encephalitis. Methods Serum and cerebrospinal fluid cytokine/chemokine levels were analysed using Procartaplex Multiplex Immunoassays. First, we analysed a panel of 32 cytokines/chemokines in a discovery group (nine aquaporin-4-antibody seropositive, nine myelin oligodendrocyte glycoprotein-antibody seropositive, eight encephalitis, 10 multiple sclerosis). Significantly dysregulated cytokines/chemokines were validated in a second cohort (11 aquaporin-4-antibody seropositive, 18 myelin oligodendrocyte glycoprotein-antibody seropositive, 18 encephalitis, 33 multiple sclerosis). Results We found 11 significantly altered cytokines/chemokines in cerebrospinal fluid and serum samples in the discovery group (a proliferation-inducing ligand, fractalkine=CX3CL1, growth-regulated oncogene-α, interleukin-1 receptor antagonist, interleukin-6, interleukin-8=CXCL8, interleukin-10, interleukin-21, interferon-ɣ-induced protein-10=CXCL10, monokine induced by interferon-ɣ=CXCL9, macrophage inflammatory protein-1ß=CCL4). Most of these cytokines/chemokines were up-regulated in autoantibodies against aquaporin-4 or autoantibodies against myelin-oligodendrocyte-glycoprotein positive patients compared to multiple sclerosis. We confirmed these results for cerebrospinal fluid interleukin-6 and serum interleukin-8, growth-regulated oncogene-α, a proliferation-inducing ligand and macrophage inflammatory protein-1β in the validation set. Receiver-operating characteristic analysis revealed increased levels of cerebrospinal fluid interleukin-6, serum interleukin-8 and growth-regulated oncogene-α in most patients with autoantibody-associated neurological diseases. Conclusion This study suggests that distinctive cerebrospinal fluid and serum cytokine/chemokine profiles are associated with autoantibody-mediated demyelination, but not with multiple sclerosis.
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17

Starble, Rebecca M., Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, and Andrew Z. Xiao. "Abstract B016: A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons." Cancer Research 82, no. 23_Supplement_2 (December 1, 2022): B016. http://dx.doi.org/10.1158/1538-7445.cancepi22-b016.

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Abstract Lung cancer is the leading cause of cancer-related death worldwide and affects over 2 million people each year. In lung adenocarcinoma (LUAD), somatic activating mutations of epidermal growth factor receptor (EGFR) occur in approximately 15% of patients. The first-line therapy for patients with EGFR-mutant LUAD is administration of osimertinib, an EGFR tyrosine kinase inhibitor (TKI). While many patients’ tumors initially respond to osimertinib treatment, resistance inevitably develops in most cases, which is a major challenge that hinders treatment efficacy. One common mechanism of resistance to osimertinib is the amplification of oncogenes, such as MET, HER2, and RET. Despite the high prevalence of oncogene amplifications in resistant tumors, the mechanisms that control oncogene amplification and transcription are poorly understood. Recent work has shown that oncogenes are frequently amplified on extrachromosomal DNA (ecDNA), which are circularized and highly amplified DNA sequences that are present in at least 14% of human cancers. Additional studies have implicated ecDNA amplification in the acquisition of resistance to TKIs, yet the mechanisms through which ecDNA is regulated are largely unknown. In the present study, we have identified a novel epigenetic factor that promotes the acquisition of TKI resistance through the organization and transcription of oncogene amplicons, some of which occur on ecDNA. To determine whether this factor binds to DNA, we used and found that it is enriched at the promoters of amplified oncogenes. Further, we performed protein immunoprecipitation followed by mass spectrometry and identified multiple candidate interacting factors, such as histone readers and components of the cohesin machinery. Depletion of this epigenetic factor prevents the acquisition of TKI resistance and leads to reduced transcription of oncogene amplicons. Thus, we propose a novel mechanism that promotes the acquisition of TKI resistance via the spatial organization and transcription of oncogene amplicons. Citation Format: Rebecca M. Starble, Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, Andrew Z. Xiao. A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B016.
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18

Sistonen, L., E. Hölttä, H. Lehväslaiho, L. Lehtola, and K. Alitalo. "Activation of the neu tyrosine kinase induces the fos/jun transcription factor complex, the glucose transporter and ornithine decarboxylase." Journal of Cell Biology 109, no. 5 (November 1, 1989): 1911–19. http://dx.doi.org/10.1083/jcb.109.5.1911.

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We have studied the ability of the neu tyrosine kinase to induce a signal for the activation of cell growth-regulated genes. Serum-starved NIH 3T3 cells expressing an epidermal growth factor receptor (EGF-R)/neu construct encoding a hybrid receptor protein were stimulated with EGF and the activation of the neu tyrosine kinase and stimulation of growth factor inducible genes were followed at the mRNA, protein, and activity levels, and compared to the corresponding responses in the neu proto-oncogene and oncogene expressing cells. Induction of the expression of jun mRNAs was an immediate early effect of EGF stimulation, followed by a marked increase in the biosynthesis of the fos/jun transcription factor complex and an increased transcription factor activity as measured by a recombinant transcription unit using chloramphenicol acetyltransferase assays. In distinction, elevated AP-1/PEA-1 activity in the absence of a significant increase in jun and fos expression was characteristic of the neu oncogene-expressing cells. The glucose transporter mRNA increased at 2 h of EGF stimulation and was associated with enhanced glucose transport of the EGF-treated cells. An increase of ornithine decarboxylase (ODC) mRNA and activity followed these changes. In contrast, serum-starved, EGF-treated neu proto-oncogene- and oncogene-expressing cells showed constitutively low and high glucose transporter and ODC activities, respectively. These findings demonstrate that the chimeric EGF-R/neu receptor is capable of activating the expression of both immediate early genes and biochemical activities associated with cell growth stimulation.
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Kang, J. S., and R. S. Krauss. "Ras induces anchorage-independent growth by subverting multiple adhesion-regulated cell cycle events." Molecular and Cellular Biology 16, no. 7 (July 1996): 3370–80. http://dx.doi.org/10.1128/mcb.16.7.3370.

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Anchorage-independent growth is a hallmark of transformed cells, but little is known of the molecular mechanisms that underlie this phenomenon. We describe here studies of cell cycle control of anchorage-independent growth induced by the ras oncogene, with the use of a somatic cell mutant fibroblast line (ER-1-2) that is specifically defective in oncogene-mediated, anchorage-independent growth. Control, nontransformed PKC3-F4 cells and ER-1-2 cells cannot proliferate in semisolid medium. Three important cell cycle events are dependent on adhesion of these cells to a substratum: phosphorylation of the retinoblastoma protein, pRB; cyclin E-dependent kinase activity; and cyclin A expression. PKC3-F4 cells that express ras (PKC3-F4/ras cells) proliferate in nonadherent cultures, and each of these three events occurs in the absence of adhesion in PKC3-F4/ras cells. Thus, ras can override the adhesion requirement of cellular functions that are necessary for cell cycle progression. ER-1-2 cells that express ras (ER-1-2/ras cells) possess hyperphosphorylated forms of pRB and cyclin E-dependent kinase activity in the absence of adhesion but remain adhesion dependent for expression of cyclin A. The adhesion dependence of pRB phosphorylation and cyclin E-dependent kinase activity is therefore dissociable from the adhesion dependence of cyclin A expression. Furthermore, ectopic expression of cyclin A is sufficient to rescue anchorage-independent growth of ER-1-2/ras cells but does not induce anchorage-independent growth of PKC3-F4 or ER-1-2 cells. However, like pRB phosphorylation and cyclin E-dependent kinase activity, the kinase activity associated with ectopically expressed cyclin A is dependent on cell adhesion, and this dependence is overcome by ras. Thus, the induction of anchorage-independent growth by ras may involve multiple signals that lead to both expression of cyclin A and activation of G1 cyclin-dependent kinase activities in the absence of cell adhesion.
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Mologni, Luca, Elisa Sala, Sara Cazzaniga, Roberta Rostagno, Thomas Kuoni, Miriam Puttini, Jenny Bain, et al. "Inhibition of RET tyrosine kinase by SU5416." Journal of Molecular Endocrinology 37, no. 2 (October 2006): 199–212. http://dx.doi.org/10.1677/jme.1.01999.

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Thyroid neoplasia is frequently associated with rearranged during transfection (RET) proto-oncogene mutations that cause hyperactivation of RET kinase activity. Selective inhibition of RET-mediated signaling should lead to an efficacious therapy. SU5416 is a potent inhibitor of vascular endothelial cell growth factor receptor, c-Kit, and FLT-3 receptor tyrosine kinases presently used in clinical trials. We found that SU5416 inhibits RET with similar potency, both in cell-free assays and in cells, thus causing proliferation arrest in oncogenic RET-transfected cells and in papillary thyroid carcinoma (PTC) cells expressing the RET/PTC1 oncogene, but not in RET-negative control cells. SU5416 inhibited RET-mediated signaling through the extracellular signal regulated kinase (ERK) and JNK pathways. In addition, we show that a naturally occurring MEN2 mutation at codon 804 confers resistance to SU5416, but not to the related compound SU4984. We provide a possible explanation to these results by using molecular docking. Finally, SU5416 was also assessed against an array of 52 tyrosine and serine/threonine kinases.
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Fan, Kaiji, Armin Zebisch, Kai Horny, David Schrama, and Jürgen C. Becker. "Highly Expressed miR-375 is not an Intracellular Oncogene in Merkel Cell Polyomavirus-Associated Merkel Cell Carcinoma." Cancers 12, no. 3 (February 25, 2020): 529. http://dx.doi.org/10.3390/cancers12030529.

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miR-375 is a highly abundant miRNA in Merkel cell carcinoma (MCC). In other cancers, it acts as either a tumor suppressor or oncogene. While free-circulating miR-375 serves as a surrogate marker for tumor burden in patients with advanced MCC, its function within MCC cells has not been established. Nearly complete miR-375 knockdown in MCC cell lines was achieved using antagomiRs via nucleofection. The cell viability, growth characteristics, and morphology were not altered by this knockdown. miR-375 target genes and related signaling pathways were determined using Encyclopedia of RNA Interactomes (ENCORI) revealing Hippo signaling and epithelial to mesenchymal transition (EMT)-related genes likely to be regulated. Therefore, their expression was analyzed by multiplexed qRT-PCR after miR-375 knockdown, demonstrating only a limited change in expression. In summary, highly effective miR-375 knockdown in classical MCC cell lines did not significantly change the cell viability, morphology, or oncogenic signaling pathways. These observations render miR-375 an unlikely intracellular oncogene in MCC cells, thus suggesting that likely functions of miR-375 for the intercellular communication of MCC should be addressed.
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Zhang, Jiayu, Liang Wu, Jiawei Chen, Sisi Lin, Daqiu Cai, Chengwei Chen, and Zhenguo Chen. "Downregulation of MicroRNA 29a/b exacerbated diabetic retinopathy by impairing the function of Müller cells via Forkhead box protein O4." Diabetes and Vascular Disease Research 15, no. 3 (February 7, 2018): 214–22. http://dx.doi.org/10.1177/1479164118756239.

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Background: Diabetic retinopathy is a neurological disease, which can lead to blindness in severe cases. The pathogenesis underlying diabetic retinopathy is unclear. The aim of this study was to explore the role of dysregulated microRNA 29a/b in the onset and progression of diabetic retinopathy. Methods: Diabetes mellitus was induced in rats using 60 mg/kg of streptozotocin. Glucose (5.5 and 25 mM) was used to stimulate rat retinal Müller cells. Real-time polymerase chain reaction and Western blot analyses were used to determine gene expression. A luciferase reporter assay was conducted to validate the relationship of microRNA 29a/b with glioma-associated oncogene homolog 1 and Forkhead box protein O4. Results: The expression of microRNA 29a/b and glutamine synthetase decreased in both diabetes mellitus rats and rat retinal Müller cells stimulated with high glucose, whereas the expression of sonic hedgehog, glioma-associated oncogene homolog 1, glial fibrillary acidic protein, and vascular endothelial growth factor, as well as the content of glutamate, increased. Dysregulated microRNA 29a/b was directly regulated by the sonic hedgehog–glioma-associated oncogene homolog 1 signalling pathway, and microRNA 29a and microRNA 29b targeted Forkhead box protein O4 and regulated its expression. Conclusion: Downregulation of microRNA 29a/b, mediated by the sonic hedgehog–glioma-associated oncogene homolog 1 signalling pathway, exacerbated diabetic retinopathy by upregulating Forkhead box protein O4.
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Saha, P., Q. Eichbaum, E. D. Silberman, B. J. Mayer, and A. Dutta. "p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases." Molecular and Cellular Biology 17, no. 8 (August 1997): 4338–45. http://dx.doi.org/10.1128/mcb.17.8.4338.

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Cdc25A, a phosphatase essential for G1-S transition, associates with, dephosphorylates, and activates the cell cycle kinase cyclin E-cdk2. p21CIP1 and p27 are cyclin-dependent kinase (cdk) inhibitors induced by growth-suppressive signals such as p53 and transforming growth factor beta (TGF-beta). We have identified a cyclin binding motif near the N terminus of Cdc25A that is similar to the cyclin binding Cy (or RR LFG) motif of the p21CIP1 family of cdk inhibitors and separate from the catalytic domain. Mutations in this motif disrupt the association of Cdc25A with cyclin E- or cyclin A-cdk2 in vitro and in vivo and selectively interfere with the dephosphorylation of cyclin E-cdk2. A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the dephosphorylation of the kinase. p21 inhibits Cdc25A-cyclin-cdk2 association and the dephosphorylation of cdk2. Conversely, Cdc25A, which is itself an oncogene up-regulated by the Myc oncogene, associates with cyclin-cdk and protects it from inhibition by p21. Cdc25A also protects DNA replication in Xenopus egg extracts from inhibition by p21. These results describe a mechanism by which the Myc- or Cdc25A-induced oncogenic and p53- or TGF-beta-induced growth-suppressive pathways counterbalance each other by competing for cyclin-cdks.
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Qu, Jianwei, Yifan Hou, Qingxiao Chen, Jing Chen, YI LI, Enfan Zhang, Huiyao Gu, et al. "ALKBH5 Functions As an Oncogene in Multiple Myeloma." Blood 138, Supplement 1 (November 5, 2021): 3326. http://dx.doi.org/10.1182/blood-2021-149622.

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Abstract Background: RNA N 6-methyladenosine (m 6A) plays a critical role in regulating gene expression and determining cell fate. The dysregulation of m 6A modulators, including α-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5), has been reported to promote tumor development through their enzymatic function. However, the functions of mRNA m 6A and its modulators in multiple myeloma (MM) are largely unknown. Methods: We queried publicly available MM datasets to study the expression profile of m 6A modulators (METTL3, METTL14, WTAP, FTO, and ALKBH5) in MM and their relationships with clinical outcomes in patients with MM. Both gain- and loss-of-function studies were performed to investigate the role of ALKBH5 in MM. The cell proliferation assay, colony formation assay, Annexin V apoptosis analysis, and 5-ethynyl-2′-deoxyuridine (EdU) assay were performed to evaluate the functions of ALKBH5 in MM in vitro. Human MM cell line xenograft models were constructed to examine the effects of ALKBH5 knockdown or overexpression on MM growth in vivo. The rescue assay using catalytically inactive mutant ALKBH5-H204A was conducted to determine whether demethylation activity was required for the function of ALKBH5 in MM. Then, we performed RNA sequencing and m 6A sequencing to explore the key targets that mediated ALKBH5 function in MM. We investigated the gene regulatory mechanism of ALKBH5 in MM by m 6A immunoprecipitation assay, RNA immunoprecipitation assay, RNA decay assay, dual-luciferase reporter assay, and so forth. Gene set enrichment analysis and Western blotting were employed to determine the downstream signaling pathways regulated by ALKBH5 and the recognized target. Results: ALKBH5 was overexpressed in MM and associated with a poor prognosis in patients with MM. The increased ALKBH5 expression was required for the survival and growth of MM cells in vitro and in vivo. Mechanistically, m 6A demethylation activity was required for ALKBH5 to exert tumorigenic effects in MM. Tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) was identified as a functionally important target of ALKBH5. ALKBH5 regulated TRAF1 expression via affecting mRNA stability of TRAF1 in an m 6A- and YTHDF2-dependent manner. ALKBH5 promoted MM cell growth and survival partly through TRAF1-mediated activation of NF-κB and MAPK signaling pathways. Conclusion: Our findings showed that ALKBH5 played an oncogenic role in MM and highlighted that ALKBH5 could potentially be a novel therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.
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Zhao, Yuxin, Zhaoxia Wang, Meili Gao, Xuehong Wang, Hui Feng, Yuanyuan Cui, and Xia Tian. "lncRNA MALAT1 regulated ATAD2 to facilitate retinoblastoma progression via miR-655-3p." Open Medicine 16, no. 1 (January 1, 2021): 931–43. http://dx.doi.org/10.1515/med-2021-0290.

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Abstract Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was reported as an oncogene in many tumors including retinoblastoma (RB). This research mainly focused on the functions and mechanism of MALAT1 in RB. MALAT1 was upregulated in RB tissues and cells, and it served as a competing endogenous RNA (ceRNA) and inhibited miRNA-655-3p (miR-655-3p) expression, which eventually regulated the expression of miR-655-3p downstream target ATPase Family AAA Domain Containing 2 (ATAD2). The level of ATAD2 significantly increased, while that of miR-655-3p remarkably decreased in RB tissues and cells. MALAT1 depletion inhibited cell proliferation, metastasis, and epithelial–mesenchymal transition (EMT), but promoted apoptosis in vitro and blocked xenograft tumor growth in vivo. MALAT1 exerted its oncogenic functions in RB by regulating miR-655-3p/ATAD2 axis.
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Yamamoto, Masayoshi, Katsuyuki Umebashi, Akinori Tokito, Junichi Imamura, and Michihisa Jougasaki. "Interleukin-33 induces growth-regulated oncogene-α expression and secretion in human umbilical vein endothelial cells." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 313, no. 3 (September 1, 2017): R272—R279. http://dx.doi.org/10.1152/ajpregu.00435.2016.

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Although interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays proinflammatory roles in immune cells as an “alarmin,” little is known regarding the biological actions of IL-33 on vascular endothelial cells. To investigate the effects of IL-33 on vascular endothelial cells, we first screened the IL-33-regulated proteins in human umbilical vein endothelial cells (HUVECs) using a dot blot array and observed that IL-33 markedly increased growth-regulated oncogene-α (GRO-α), a chemokine that is also known as chemokine (C-X-C motif) ligand 1 (CXCL1). Real-time reverse transcription PCR and ELISA demonstrated that IL-33 induced GRO-α expression and secretion in HUVECs in a dose- and a time-dependent manner. Western immunoblot assay revealed that IL-33 activated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2 -terminal kinase (JNK). In addition, translocation of nuclear factor-κB (NF-κB) p65 to the nucleus of HUVECs was observed by IL-33 stimulation. Furthermore, treatment with pharmacological inhibitors against ERK1/2 (PD98059), JNK (SP600125), or NF-κB (BAY11-7085) significantly suppressed IL-33-induced GRO-α gene expression and secretion from HUVECs. Moreover, immunohistochemical staining demonstrated that IL-33 and GRO-α coexpressed in the endothelium of human carotid atherosclerotic plaque. Taken together, the present study indicates that IL-33 localized in the human atherosclerotic plaque increases GRO-α mRNA expression and protein secretion via activation of ERK1/2, JNK, and NF-κB in HUVECs, suggesting that IL-33 plays an important role in the pathophysiology and development of atherosclerosis.
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Pollett, Jonathan B., Suzanne Trudel, Daniel Stern, Zhixiong H. Li, and A. Keith Stewart. "Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance." Blood 100, no. 10 (November 15, 2002): 3819–21. http://dx.doi.org/10.1182/blood-2002-02-0608.

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Translocations involving the immunoglobulin heavy-chain switch region and fibroblast growth factor receptor 3 (FGFR3) are identified in 10% to 15% of patients with myeloma. In previous research we overexpressed FGFR3 or the constitutively active FGFR3-TD mutant in an interleukin-6 (IL-6)–dependent murine myeloma cell line, B9. FGFR3-enhanced IL-6 responsiveness increased phosphorylation of STAT3 and up-regulated Bcl-xL. Since Bcl-xL was up-regulated, we have tested FGFR3-expressing B9 cells for chemotherapy sensitivity. FGFR3 expression did not alter sensitivity to melphalan or doxorubicin. In contrast, B9 cells overexpressing FGFR3 were resistant to treatment with dexamethasone, a phenomenon successfully reversed using a Bcl-xL antisense oligonucleotide. These data demonstrate that the overexpression of FGFR3 in B9 cells confers resistance to dexamethasone but not to anthracyclines or alkylating agents, at least in part through the up-regulation of Bcl-xL. This finding has potential implications for the use of chemotherapy in t(4;14)-positive myeloma.
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Wu, Yu, Ruixue Sun, and Yan Lun. "Pim-1, Beyond an Oncogene, in Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 4979. http://dx.doi.org/10.1182/blood.v126.23.4979.4979.

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Abstract Background and Objective: There are 3 members in Pim family, Pim-1, Pim-2 and Pim-3. They are serine/threonine kinase coding proto-oncogene. It is reported that Pim-1 plays a role in solid tumor, leukemia and polycythemia vera, et al. Pim-3, as a newly cloned oncogene has discovered to functioning in hepatic carcinoma, pancreatic cancer, et al. We are trying to find out the roles of Pim1 in acute myeloid leukemia. Methods: 1 Evaluate the expressions of Pim family genes in acute myeloid leukemia patients and analysis the profile of Pim expressions with clinical characteristics. 2 Up-regulating the expression of Pim1 in AML cell lines by transient transfection or long-term infection through GFP-expressing plasmids and lenti-virus system and analyze the proliferation, apoptosis and chemotaxis features of the transfected AML cell lines. Results: 1 Our investigation showed that Pim-1 is up-regulated in around 15% of acute myeloid leukemia (AML) patients. 2 As shown in growth curves and apoptosis assays, over expression of Pim-1induces growth up-regulation and anti-apoptosis. We hypothesized that phenomenon could be originated from the enhanced expression of c-myc, cyclin D1 and Bad phosphorylation shown in western blotting analysis. 3 Our chemotaxis assay and bone marrow stromal cell co-culture model demonstrated that overexpression of Pim-1can enhance the AML cells chemotactic movement toward SDF-1¦Á, with calcium influx increment and phosphorylation of CXCR4. 4 Flow cytometry analysis and confocal immunofluorescence observation demonstrated the up-regulated CXCR4 expression and internalization induced by SDF-1¦Á. 5 We also checked the angiogenesis and adhesion molecule during the process but did not show any contribution. Conclusion: Pim-1, beyond as an oncogene, can promote growth or anti-apoptosis of AML cells, can interact with microenviroment through SDF-1¦Á-CXCR4 axis. The interplay between AML cells and microenviroment mediated by Pim-1 can make sense in AML target therapy and make a good adjunctive for transplantation conditioning regimen. Figure 1. Expression of Pim1 in AML patients and control Figure 1. Expression of Pim1 in AML patients and control Disclosures No relevant conflicts of interest to declare.
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Hideshima, Teru, Constantine Mitsiades, Hiroshi Ikeda, Dharminder Chauhan, Noopur Raje, Gullu Gorgun, Hiromasa Hideshima, et al. "A proto-oncogene BCL6 is up-regulated in the bone marrow microenvironment in multiple myeloma cells." Blood 115, no. 18 (May 6, 2010): 3772–75. http://dx.doi.org/10.1182/blood-2010-02-270082.

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Abstract Constitutive B-cell lymphoma 6 (Bcl-6) expression was undetectable in multiple myeloma (MM) cell lines, except U266 cells. However, it was up-regulated by coculture with bone marrow (BM) stromal cell-culture supernatant (SCCS). Bcl-6 expression in patient MM cells in the BM was positive. Anti–interleukin-6 (IL-6)–neutralizing antibody significantly blocked SCCS-induced Bcl-6 in MM cells. Indeed, IL-6 strongly triggered Bcl-6 expression in MM cells, whereas Janus kinase inhibitor and STAT3 siRNA down-regulated Bcl-6. Tumor necrosis factor-α (TNF-α) also triggered Bcl-6, but independently of STAT3, whereas IκB kinaseβ inhibitor down-regulated TNF-α–induced Bcl-6, indicating that the canonical nuclear factor-κB pathway mediates TNF-α–induced Bcl-6 expression. Importantly, down-regulation of Bcl-6 by shRNA significantly inhibited MM cell growth in the presence of SCCS. Our results therefore suggest that Bcl-6 expression in MM cells is modulated, at least in part, via Janus kinase/STAT3 and canonical nuclear factor-κB pathways and that targeting Bcl-6, either directly or via these cascades, inhibits MM cell growth in the BM milieu.
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Ying, Xiaomei, Liang Chen, Jiaheng Xie, Yiming Hu, Qingqing Wu, Liyu Cao, and Hongzhu Yu. "ANXA1 (Annexin A1) regulated by MYC (MYC proto-oncogene) promotes the growth of papillary thyroid carcinoma." Bioengineered 12, no. 2 (December 20, 2021): 9251–65. http://dx.doi.org/10.1080/21655979.2021.1996511.

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Ye, Mei‐Yin, Meng‐Yen Chen, Ya‐Han Chang, Jehn‐Shyun Huang, Tze‐Ta Huang, Tung‐Yiu Wong, Tse‐Ming Hong, and Yuh‐Ling Chen. "Growth‐regulated oncogene‐α from oral submucous fibrosis fibroblasts promotes malignant transformation of oral precancerous cells." Journal of Oral Pathology & Medicine 47, no. 9 (August 6, 2018): 880–86. http://dx.doi.org/10.1111/jop.12768.

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Li, Jing, and Neil Sidell. "Growth-related oncogene produced in human breast cancer cells and regulated by Syk protein-tyrosine kinase." International Journal of Cancer 117, no. 1 (2005): 14–20. http://dx.doi.org/10.1002/ijc.21074.

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33

Cleveland, J. L., M. Dean, N. Rosenberg, J. Y. Wang, and U. R. Rapp. "Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl." Molecular and Cellular Biology 9, no. 12 (December 1989): 5685–95. http://dx.doi.org/10.1128/mcb.9.12.5685-5695.1989.

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Retroviral expression vectors carrying the tyrosine kinase oncogenes abl, fms, src, and trk abrogate the requirements of murine myeloid FDC-P1 cells for interleukin-3 (IL-3). Factor-independent clones constitutively express c-myc in the absence of IL-3, whereas in parental cultures c-myc transcription requires the presence of the ligand. To directly test the effect of a tyrosine kinase oncogene on c-myc expression, retroviral constructs containing three different temperature-sensitive mutants of v-abl were introduced into myeloid IL-3-dependent FDC-P1 and 32D cells. At the permissive temperature, clones expressing temperature-sensitive abl behaved like wild-type abl-containing cells in their growth properties and expressed c-myc constitutively. Temperature shift experiments demonstrated that both IL-3 abrogation and the regulation of c-myc expression correlated with the presence of functional v-abl. Induction of c-myc expression by reactivation of temperature-sensitive v-abl mimicked c-myc induction by IL-3 in that it did not require protein synthesis and occurred at the level of transcription, with effects on both initiation and a transcription elongation block. However, v-abl-regulated FDC-P1 cell growth differed from IL-3-regulated growth in that c-fos and junB, which are normally induced by IL-3, were not induced by activation of v-abl.
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Cleveland, J. L., M. Dean, N. Rosenberg, J. Y. Wang, and U. R. Rapp. "Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl." Molecular and Cellular Biology 9, no. 12 (December 1989): 5685–95. http://dx.doi.org/10.1128/mcb.9.12.5685.

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Retroviral expression vectors carrying the tyrosine kinase oncogenes abl, fms, src, and trk abrogate the requirements of murine myeloid FDC-P1 cells for interleukin-3 (IL-3). Factor-independent clones constitutively express c-myc in the absence of IL-3, whereas in parental cultures c-myc transcription requires the presence of the ligand. To directly test the effect of a tyrosine kinase oncogene on c-myc expression, retroviral constructs containing three different temperature-sensitive mutants of v-abl were introduced into myeloid IL-3-dependent FDC-P1 and 32D cells. At the permissive temperature, clones expressing temperature-sensitive abl behaved like wild-type abl-containing cells in their growth properties and expressed c-myc constitutively. Temperature shift experiments demonstrated that both IL-3 abrogation and the regulation of c-myc expression correlated with the presence of functional v-abl. Induction of c-myc expression by reactivation of temperature-sensitive v-abl mimicked c-myc induction by IL-3 in that it did not require protein synthesis and occurred at the level of transcription, with effects on both initiation and a transcription elongation block. However, v-abl-regulated FDC-P1 cell growth differed from IL-3-regulated growth in that c-fos and junB, which are normally induced by IL-3, were not induced by activation of v-abl.
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35

Xu, Lifeng, Ryan B. Corcoran, James W. Welsh, Diane Pennica, and Arnold J. Levine. "WISP-1 is a Wnt-1- and β-catenin-responsive oncogene." Genes & Development 14, no. 5 (March 1, 2000): 585–95. http://dx.doi.org/10.1101/gad.14.5.585.

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WISP-1 (Wnt-1 induced secreted protein 1) is a member of the CCN family of growth factors. This study identifies WISP-1 as a β-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and β-catenin expression. TCF/LEF sites played a minor role, whereas the CREB site played an important role in this transcriptional activation. WISP-1 demonstrated oncogenic activities; overexpression of WISP-1 in normal rat kidney fibroblast cells (NRK-49F) induced morphological transformation, accelerated cell growth, and enhanced saturation density. Although these cells did not acquire anchorage-independent growth in soft agar, they readily formed tumors in nude mice, suggesting that appropriate cellular attachment is important for signaling oncogenic events downstream of WISP-1.
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Liu, Xianqiong, Junjie Hu, Xinhua Song, Kirsten Utpatel, Yi Zhang, Pan Wang, Xinjun Lu, et al. "Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma." Cancers 11, no. 7 (July 3, 2019): 930. http://dx.doi.org/10.3390/cancers11070930.

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Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and oncogene c-mesenchymal-epithelial transition (c-Met) proto-oncogenes in the mouse liver via hydrodynamic tail vein injection (AKT/c-MET mice). Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC. Methods: Here, we investigated the therapeutic efficacy of sorafenib, regorafenib, the MEK inhibitor PD901 as well as the pan-mTOR inhibitor MLN0128 in the AKT/c-Met preclinical HCC model. Results: In these mice, neither sorafenib nor regorafenib demonstrated any efficacy. In contrast, administration of PD901 inhibited cell cycle progression of HCC cells in vitro. Combined PD901 and MLN0128 administration resulted in a pronounced growth constraint of HCC cell lines. In vivo, treatment with PD901 or MLN0128 alone moderately slowed HCC growth in AKT/c-MET mice. Importantly, the simultaneous administration of the two drugs led to a stable disease with limited tumor progression in mice. Mechanistically, combined mitogen-activated extracellular signal-regulated kinase (MEK) and mTOR inhibition resulted in a stronger cell cycle inhibition and growth arrest both in vitro and in vivo. Conclusions: Our study indicates that combination of MEK and mTOR inhibitors might represent an effective therapeutic approach against human HCC.
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Li, Jie, Shaohui Zhou, Hongchen Li, Yanzhao Xu, Ning Zhou, and Rongfeng Liu. "PTEN/AKT upregulation of TMSB10 contributes to lung cancer cell growth and predicts poor survival of the patients." Bioscience, Biotechnology, and Biochemistry 85, no. 4 (December 29, 2020): 805–13. http://dx.doi.org/10.1093/bbb/zbaa113.

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ABSTRACT PTEN/AKT signaling cascade is frequently activated in various cancers, including lung cancer. The downstream effector of this signaling cascade is poorly understood. β-Thymosin 10 (TMSB10) functions as an oncogene or tumor suppressors in cancers, whereas its significance in lung cancer remains unknown. In this study, we showed that the activation of PTEN/AKT signaling promoted the expression of TMSB10. Based on the TCGA database, TMSB10 was upregulated in lung cancer tissues and its overexpression was correlated with poor prognosis of lung cancer patients. Functional experiments demonstrated that TMSB10 knockdown suppressed, while its overexpression promoted the proliferation, growth, and migration of lung cancer cells. Apoptosis and epithelial-mesenchymal transition were also regulated by TMSB10. We therefore suggest that TMSB10 is a novel oncogene for lung cancer. Targeting TMSB10 may benefit lung cancer patients with activated PTEN/AKT signaling.
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Sander, Sandrine, Lars Bullinger, Kay Klapproth, Katja Fiedler, Hans A. Kestler, Thomas F. E. Barth, Peter Möller, Stephan Stilgenbauer, Jonathan R. Pollack, and Thomas Wirth. "MYC stimulates EZH2 expression by repression of its negative regulator miR-26a." Blood 112, no. 10 (November 15, 2008): 4202–12. http://dx.doi.org/10.1182/blood-2008-03-147645.

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Abstract The MYC oncogene, which is commonly mutated/amplified in tumors, represents an important regulator of cell growth because of its ability to induce both proliferation and apoptosis. Recent evidence links MYC to altered miRNA expression, thereby suggesting that MYC-regulated miRNAs might contribute to tumorigenesis. To further analyze the impact of MYC-regulated miRNAs, we investigated a murine lymphoma model harboring the MYC transgene in a Tet-off system to control its expression. Microarray-based miRNA expression profiling revealed both known and novel MYC targets. Among the miRNAs repressed by MYC, we identified the potential tumor suppressor miR-26a, which possessed the ability to attenuate proliferation in MYC-dependent cells. Interestingly, miR-26a was also found to be deregulated in primary human Burkitt lymphoma samples, thereby probably being of clinical relevance. Although today only few miRNA targets have been identified in human disease, we could show that ectopic expression of miR-26a influenced cell cycle progression by targeting the bona fide oncogene EZH2, a Polycomb protein and global regulator of gene expression yet unknown to be regulated by miRNAs. Thus, in addition to directly targeting protein-coding genes, MYC modulates genes important to oncogenesis via deregulation of miRNAs, thereby vitally contributing to MYC-induced lymphomagenesis.
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Shintani, Satoru, Tohru Ishikawa, Tomoko Nonaka, Chunnan Li, Koh-ichi Nakashiro, David T. W. Wong, and Hiroyuki Hamakawa. "Growth-Regulated Oncogene-1 Expression Is Associated with Angiogenesis and Lymph Node Metastasis in Human Oral Cancer." Oncology 66, no. 4 (2004): 316–22. http://dx.doi.org/10.1159/000078333.

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Gouw, Arvin M., Katherine Margulis, Natalie S. Liu, Sudha J. Raman, Anthony Mancuso, Georgia G. Toal, Ling Tong, et al. "The MYC Oncogene Cooperates with Sterol-Regulated Element-Binding Protein to Regulate Lipogenesis Essential for Neoplastic Growth." Cell Metabolism 30, no. 3 (September 2019): 556–72. http://dx.doi.org/10.1016/j.cmet.2019.07.012.

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Shetzline, Susan E., Ravikumar Rallapalli, Kelley J. Dowd, Shaomin Zou, Yuji Nakata, Cezary R. Swider, Anna Kalota, John K. Choi, and Alan M. Gewirtz. "Neuromedin U: a Myb-regulated autocrine growth factor for human myeloid leukemias." Blood 104, no. 6 (September 15, 2004): 1833–40. http://dx.doi.org/10.1182/blood-2003-10-3577.

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Abstract The c-myb proto-oncogene has been implicated in leukemogenesis, but possible mechanisms remain ill defined. To gain further insight to this process, we used transcript profiling in K562 cells expressing a dominant-negative Myb (MERT) protein. A total of 105 potential Myb gene targets were identified. Neuromedin U (NmU), a peptide affecting calcium transport, underwent the greatest expression change (∼ 5-fold decrease). To verify a linkage between c-myb and NmU, their mRNA levels were quantitated using real-time polymerase chain reaction in primary acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), as well as normal hematopoietic cells. We found that c-myb was elevated in AML and ALL samples, but NmU expression was increased only in AML cells. Significantly, only AML cells expressed the cognate receptor of NmU, NMU1R, suggesting the presence of a novel autocrine loop. We examined this possibility in detail. Exogenous NmU “rescued” growth suppression in K562-MERT cells and stimulated the growth of primary AML cells. Short interfering RNA “knockdown” of NmU in K562 cells arrested cell growth. Exposing Indo-1–labeled K562 cells to NmU induced an intracellular Ca++ flux consistent with engagement of the NMU1R. Combined, these results suggest that NmU expression is related to Myb and that the NmU/NMU1R axis constitutes a previously unknown growth-promoting autocrine loop in myeloid leukemia cells.
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Madan, Babita, Matthew P. Walker, Robert Young, Laura Quick, Kelly A. Orgel, Meagan Ryan, Priti Gupta, et al. "USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds." Proceedings of the National Academy of Sciences 113, no. 21 (May 9, 2016): E2945—E2954. http://dx.doi.org/10.1073/pnas.1605691113.

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The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/β-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit.
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43

Rentschler, Maximilian, Yan Chen, Jana Pahl, Laura Soria-Martinez, Heidi Braumüller, Ellen Brenner, Oliver Bischof, Martin Röcken, and Thomas Wieder. "Nuclear Translocation of Argonaute 2 in Cytokine-Induced Senescence." Cellular Physiology and Biochemistry 51, no. 3 (2018): 1103–18. http://dx.doi.org/10.1159/000495490.

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Background/Aims: Cellular senescence, or permanent growth arrest, is known as an effective tumor suppressor mechanism that can be induced by different stressors, such as oncogenes, chemotherapeutics or cytokine cocktails. Previous studies demonstrated that the growth-repressing state of oncogene-induced senescent cells depends on argonaute protein 2 (Ago2)-mediated transcriptional gene silencing and Ago2/Rb corepression of E2F-dependent cell cycle genes. Cytokine-induced senescence (CIS) likewise depends on activation of the p16Ink4a/Rb pathway, and consecutive inactivation of the E2F family of transcription factors. In the present study, we therefore analyzed the role of Ago2 in CIS. Methods: Human cancer cell lines were treated with interferon-gamma (IFN-γ) and tumor necrosis factor (TNF) to induce senescence. Senescence was determined by growth assays and measurement of senescence-associated β-galactosidase (SA-β-gal) activity, Ago2 translocation by Ago2/ Ki67 immunofluorescence staining and western blot analysis, and gene transcription by quantitative polymerase chain reaction (qPCR). Results: IFN-γ and TNF permanently stopped cell proliferation and time-dependently increased SA-β-gal activity. After 24 – 48 h of cytokine treatment, Ago2 translocated from the cytoplasm into the nucleus of Ki67-negative cells, an effect which was shown to be reversible. Importantly, the proinflammatory cytokine cocktail suppressed Ago2-regulated cell cycle control genes, and siRNA-mediated depletion of Ago2 interfered with cytokine-induced growth inhibition. Conclusion: IFN-γ and TNF induce a stable cell cycle arrest of cancer cells that is accompanied by a fast nuclear Ago2 translocation and repression of Ago2-regulated cell cycle control genes. As Ago2 downregulation impairs cytokine-induced growth regulation, Ago2 may contribute to tissue homeostasis in human cancers.
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44

Lian, Shuijin, Xiaolu Zhai, Xudong Wang, Huijun Zhu, Shu Zhang, Wei Wang, Zhiwei Wang, and Jianfei Huang. "Elevated expression of growth-regulated oncogene-alpha in tumor and stromal cells predicts unfavorable prognosis in pancreatic cancer." Medicine 95, no. 30 (July 2016): e4328. http://dx.doi.org/10.1097/md.0000000000004328.

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45

Johansen, H., A. van der Straten, R. Sweet, E. Otto, G. Maroni, and M. Rosenberg. "Regulated expression at high copy number allows production of a growth-inhibitory oncogene product in Drosophila Schneider cells." Genes & Development 3, no. 6 (June 1, 1989): 882–89. http://dx.doi.org/10.1101/gad.3.6.882.

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46

Fukuda, Junichiro, Kaei Nasu, Bing Sun, Shinichiro Mine, Yasushi Kawano, and Isao Miyakawa. "Expression of growth-regulated oncogene β in an endometrial epithelial cell line, HHUA, and cultured human endometrial cells." Journal of Reproductive Immunology 59, no. 1 (June 2003): 61–70. http://dx.doi.org/10.1016/s0165-0378(02)00082-7.

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47

Ledwith, B. J., S. Manam, A. R. Kraynak, W. W. Nichols, and M. O. Bradley. "Antisense-fos RNA causes partial reversion of the transformed phenotypes induced by the c-Ha-ras oncogene." Molecular and Cellular Biology 10, no. 4 (April 1990): 1545–55. http://dx.doi.org/10.1128/mcb.10.4.1545-1555.1990.

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Several lines of evidence have suggested that c-fos may act downstream from c-Ha-ras in a growth-regulatory signal transduction pathway. We used antisense RNA to inhibit c-fos gene expression and investigated the effects of diminished c-fos expression on the phenotypes induced by the EJ c-Ha-ras oncogene in NIH 3T3 cells. Immunofluorescent staining demonstrated that the antisense RNA caused a marked reduction in the amount of c-fos protein expressed following serum stimulation. EJ cells containing antisense-fos RNA continued to overexpress ras and remained capable of proliferating in vitro. However, the antisense-fos RNA caused a partial reversion of the major transformed phenotypes of EJ cells, including a restoration of both density-dependent growth arrest and the ability to be rendered quiescent by serum deprivation, a reversion to a flat morphology, inhibition of anchorage-independent growth, and inhibition of tumorigenicity in nude mice. Our results indicate that inhibition of c-fos expression, to a level still supporting in vitro proliferation, prevents the transforming effects of the ras oncogene; they thus provide additional evidence for the participation of c-fos in ras-regulated signal transduction pathways.
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48

Ledwith, B. J., S. Manam, A. R. Kraynak, W. W. Nichols, and M. O. Bradley. "Antisense-fos RNA causes partial reversion of the transformed phenotypes induced by the c-Ha-ras oncogene." Molecular and Cellular Biology 10, no. 4 (April 1990): 1545–55. http://dx.doi.org/10.1128/mcb.10.4.1545.

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Abstract:
Several lines of evidence have suggested that c-fos may act downstream from c-Ha-ras in a growth-regulatory signal transduction pathway. We used antisense RNA to inhibit c-fos gene expression and investigated the effects of diminished c-fos expression on the phenotypes induced by the EJ c-Ha-ras oncogene in NIH 3T3 cells. Immunofluorescent staining demonstrated that the antisense RNA caused a marked reduction in the amount of c-fos protein expressed following serum stimulation. EJ cells containing antisense-fos RNA continued to overexpress ras and remained capable of proliferating in vitro. However, the antisense-fos RNA caused a partial reversion of the major transformed phenotypes of EJ cells, including a restoration of both density-dependent growth arrest and the ability to be rendered quiescent by serum deprivation, a reversion to a flat morphology, inhibition of anchorage-independent growth, and inhibition of tumorigenicity in nude mice. Our results indicate that inhibition of c-fos expression, to a level still supporting in vitro proliferation, prevents the transforming effects of the ras oncogene; they thus provide additional evidence for the participation of c-fos in ras-regulated signal transduction pathways.
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49

Hole, Paul S., Lorna Pearn, Amanda J. Tonks, Philip E. James, Alan K. Burnett, Richard L. Darley, and Alex Tonks. "Ras-induced reactive oxygen species promote growth factor–independent proliferation in human CD34+ hematopoietic progenitor cells." Blood 115, no. 6 (February 11, 2010): 1238–46. http://dx.doi.org/10.1182/blood-2009-06-222869.

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Abstract Excessive production of reactive oxygen species (ROS) is a feature of human malignancy and is often triggered by activation of oncogenes such as activated Ras. ROS act as second messengers and can influence a variety of cellular process including growth factor responses and cell survival. We have examined the contribution of ROS production to the effects of N-RasG12D and H-RasG12V on normal human CD34+ progenitor cells. Activated Ras strongly up-regulated the production of both superoxide and hydrogen peroxide through the stimulation of NADPH oxidase (NOX) activity, without affecting the expression of endogenous antioxidants or the production of mitochondrially derived ROS. Activated Ras also promoted both the survival and the growth factor–independent proliferation of CD34+ cells. Using oxidase inhibitors and antioxidants, we found that excessive ROS production by these cells did not contribute to their enhanced survival; rather, ROS promoted their growth factor–independent proliferation. Although Ras-induced ROS production specifically activated the p38MAPK oxidative stress response, this failed to induce expression of the cell-cycle inhibitor, p16INK4A; instead, ROS promoted the expression of D cyclins. These data are the first to show that excessive ROS production in the context of oncogene activation can promote proliferative responses in normal human hematopoietic progenitor cells.
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50

Berezovsky, Artem, Indrani Datta, Ruicong She, Andrea Transou, Susan Irtenkauf, Laura Hasselbach, Laila Poisson, and Ana deCarvalho. "CSIG-10. PLATELET-DERIVED GROWTH FACTOR RECEPTOR ALPHA ONCOGENE DEPENDENCY IN GLIOBLASTOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi35. http://dx.doi.org/10.1093/neuonc/noab196.136.

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Abstract PDGFRA is the second most frequently amplified gene encoding receptor tyrosine kinase in adult glioblastoma (GBM), oftentimes as extrachromosomal elements (ecDNA). Our overall objective is to elucidate mechanisms underlying PDGFRα dependency in GBM tumor maintenance. We have isolated distinct subpopulations from a GBM model (HF3253), harboring two alterations in PDGFRA: constitutively active genomic rearrangement and extrachromosomal amplification, that differ in the frequency of PDGFRA ecDNA. HF3253 tumor growth rate correlates with the initial proportion of ecDNA+ population implanted. Furthermore, slower tumor growth is due to selection for initially low-frequency PDGFRA ecDNA amplified clones based on histology and TaqMan Copy Number assay. Further exploiting intra-tumoral heterogeneity, we have isolated single cell clones from bulk cells. Compared to bulk cells, single cell clones do not express PDGFRα, PDGFRA mRNA and exhibit diploid PDGFRA copy number. Tumor growth was reduced in 4 ecDNA(-) clones compared to parental ecDNA(+) (log-rank test p= 0.00772, 0.00379, 0.00076, 0.00379). In contrast to parental HF3253, ecDNA(-) tumors demonstrated diffuse tumor morphology and weak PDGFRα activation. HF3253 ecDNA(-) PDX tumors lack detectable PDGFRα. Correspondingly, HF3253 ecDNA(-) cell populations do not exhibit de novo PDGFRA copy number gains post-implant. We conducted paired, whole RNA-sequencing on 20 HF3253 populations (ecDNA+/-: 6 clones from 3 biological replicates PDXs and 4 clones from 4 in vitro technical replicates). Employing a false discovery rate of 0.05, we identified 785 differentially expressed genes. Platelet-derived growth factor binding (GO:0048407) and central carbon metabolism were down-regulated in ecDNA(-) while genes significantly associated with astrocytic processes were upregulated. We demonstrated the dependency on PDGFRα signaling in a patient-derived GBM model carrying ecDNA PDGFRA amplification. Our data validates PDGFRɑ as a therapeutic target in a subset of GBM patients and demonstrates that detection of ecDNA-amplified PDGFRA has the potential to be a predictive biomarker of future PDGFRɑ targeted therapies.
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