Journal articles: 'Modulation of oncogene expression'

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Seldin, M. F., J. D. Mountz, J. F. Mushinski, H. R. Smith, and A. D. Steinberg. "IL-2 Modulation of Murine T-Cell Oncogene Expression." Experimental Biology and Medicine 184, no. 2 (February 1, 1987): 186–90. http://dx.doi.org/10.3181/00379727-184-42465.

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Harel-Bellan, Annick, and William L. Farrar. "Modulation of proto-oncogene expression by colony stimulating factors." Biochemical and Biophysical Research Communications 148, no. 3 (November 1987): 1001–8. http://dx.doi.org/10.1016/s0006-291x(87)80231-0.

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Spirin, P. V., N. A. Nikitenko, T. D. Lebedev, P. M. Rubtsov, C. Stocking, and V. S. Prasolov. "Modulation of activated oncogene c-kit expression with RNA-interference." Molecular Biology 45, no. 6 (December 2011): 950–58. http://dx.doi.org/10.1134/s0026893311060136.

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Sarno, Federica, Désirée Goubert, Emilie Logie, Martijn G. S. Rutten, Mihaly Koncz, Christophe Deben, Anita E. Niemarkt, et al. "Functional Validation of the Putative Oncogenic Activity of PLAU." Biomedicines 11, no. 1 (December 30, 2022): 102. http://dx.doi.org/10.3390/biomedicines11010102.

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Plasminogen activator, urokinase (PLAU) is involved in cell migration, proliferation and tissue remodeling. PLAU upregulation is associated with an increase in aggressiveness, metastasis, and invasion of several cancer types, including breast cancer. In patients, this translates into decreased sensitivity to hormonal treatment, and poor prognosis. These clinical findings have led to the examination of PLAU as a biomarker for predicting breast cancer prognosis and therapy responses. In this study, we investigated the functional ability of PLAU to act as an oncogene in breast cancers by modulating its expression using CRISPR-deactivated Cas9 (CRISPR-dCas9) tools. Different effector domains (e.g., transcription modulators (VP64, KRAB)) alone or in combination with epigenetic writers (DNMT3A/3L, MSssI) were fused to dCas9 and targeted to the PLAU promoter. In MDA-MB-231 cells characterized by high PLAU expression downregulation of PLAU expression by CRISPR-dCas9-DNMT3A/3L-KRAB, resulted in decreased cell proliferation. Conversely, CRISPR-dCas9-VP64 induced PLAU upregulation in low PLAU expressing MCF-7 cells and significantly increased aggressiveness and invasion. In conclusion, modulation of PLAU expression affected metastatic related properties of breast cancer cells, thus further validating its oncogenic activity in breast cancer cells.

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Kakhlon, O., Y. Gruenbaum, and Z. I. Cabantchik. "Repression of ferritin expression modulates cell responsiveness to H-ras-induced growth." Biochemical Society Transactions 30, no. 4 (August 1, 2002): 777–80. http://dx.doi.org/10.1042/bst0300777.

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We assessed the role of the cell labile iron pool in mediating oncogene-induced cell proliferation via repression of ferritin expression. When HEK-293 cells, engineered to inducibly express either active (+) or dominant-negative (-) forms of the H-ras oncogene, were treated with antisense nucleotides to ferritin subunits they displayed (a) decreased ferritin levels, (b) increased labile iron pool and either (c) faster growth in cells induced to express H-Ras (+) or (d) recovery from growth retardation in dominant-negative H-Ras-induced cells. Our studies support the view that the role of down-modulation of ferritin expression by some oncogene-evoked proliferation proceeds via expansion of the cellular labile iron pool.

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Lehtola, L., M. Nistér, E. Hölttä, B. Westermark, and K. Alitalo. "Down-regulation of cellular platelet-derived growth factor receptors induced by an activated neu receptor tyrosine kinase." Cell Regulation 2, no. 8 (August 1991): 651–61. http://dx.doi.org/10.1091/mbc.2.8.651.

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The functional integration of growth factor signaling occurs at several levels in target cells. One of the most proximal mechanisms is receptor transmodulation, by which one activated receptor can regulate the expression of other receptors in the same cells. Well-established transregulatory loops involve platelet-derived growth factor (PDGF) down-regulation of epidermal growth factor (EGF) receptors and beta-type transforming growth factors modulation of PDGF receptors. We have studied the relationship between neu tyrosine kinase activation and the expression of the PDGF receptors in transfected NIH/3T3 cells. Expression of the neu oncogene, but not of the neu proto-oncogene, was associated with a decrease of PDGF alpha- and beta-receptors on the cell surface, as measured by [125-I]PDGF-AA and -BB binding. These results were corroborated by metabolic labeling and immunoprecipitation of the PDGF beta-receptors. PDGF alpha- and beta-receptor mRNAs were strongly decreased in the neu oncogene-transformed cells in comparison with control cells expressing the neu proto-oncogene. Down-regulation of the PDGF receptors and their mRNAs was also observed after EGF treatment of cells expressing a chimeric EGF receptor/neu receptor, where the neu tyrosine kinase is activated by EGF binding. These results show that the neu tyrosine kinase can down-modulate PDGF receptor expression, and the effect is mediated via decreased PDGF receptor mRNA levels.

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Bell, S. M., D. C. Connolly, N. J. Maihle, and J. L. Degen. "Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases." Molecular and Cellular Biology 13, no. 9 (September 1993): 5888–97. http://dx.doi.org/10.1128/mcb.13.9.5888-5897.1993.

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Urokinase-type plasminogen activator (uPA) gene transcription is increased > or = 50-fold in chicken embryo fibroblasts (CEF) following transformation by the protein tyrosine kinase pp60v-src. Protein phosphorylation appears to play a critical role in uPA gene expression in these cells; protein kinase C-activating phorbol esters cooperate with pp60v-src to synergistically increase uPA mRNA, whereas cyclic AMP (cAMP)-dependent protein kinase-activating agents (e.g., 8-bromo cAMP) repress uPA mRNA levels. To explore the relationship between transforming oncogenes and uPA gene expression, uPA mRNA levels were measured in CEF infected with selected avian retroviruses. We report that v-ras and the transforming protein tyrosine kinases v-src, v-yes, and v-ros all increase cellular uPA mRNAs. However, transformation with the protein tyrosine kinase encoded by v-erbB, or the nuclear proteins encoded by v-jun, v-ski, or v-myc, did not increase uPA mRNA detectably. Ras and all of the protein tyrosine kinases analyzed, including the v-erbB product, but none of the nuclear oncoproteins sensitized cells to phorbol ester induction of uPA gene expression. Thus, increased uPA gene expression is not simply a secondary consequence of cell transformation but, rather, is regulated or comodulated by only a subset of oncogene products. Analysis of cells expressing site-directed mutants of pp60v-src showed that the induction of the uPA gene is dependent on protein tyrosine kinase catalytic activity, myristylation, and plasma membrane localization. However, these properties together are not sufficient; an additional feature in the src homology 2 domain is also required. The major sites of serine phosphorylation, serines 12 and 17, and the autophosphorylation site, tyrosine 416, are not essential for uPA gene induction. However, the reduction of uPA mRNA in pp60v-src-transformed cells by 8-bromo cAMP is dependent on tyrosine 416.

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Bell, S. M., D. C. Connolly, N. J. Maihle, and J. L. Degen. "Differential modulation of plasminogen activator gene expression by oncogene-encoded protein tyrosine kinases." Molecular and Cellular Biology 13, no. 9 (September 1993): 5888–97. http://dx.doi.org/10.1128/mcb.13.9.5888.

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Urokinase-type plasminogen activator (uPA) gene transcription is increased > or = 50-fold in chicken embryo fibroblasts (CEF) following transformation by the protein tyrosine kinase pp60v-src. Protein phosphorylation appears to play a critical role in uPA gene expression in these cells; protein kinase C-activating phorbol esters cooperate with pp60v-src to synergistically increase uPA mRNA, whereas cyclic AMP (cAMP)-dependent protein kinase-activating agents (e.g., 8-bromo cAMP) repress uPA mRNA levels. To explore the relationship between transforming oncogenes and uPA gene expression, uPA mRNA levels were measured in CEF infected with selected avian retroviruses. We report that v-ras and the transforming protein tyrosine kinases v-src, v-yes, and v-ros all increase cellular uPA mRNAs. However, transformation with the protein tyrosine kinase encoded by v-erbB, or the nuclear proteins encoded by v-jun, v-ski, or v-myc, did not increase uPA mRNA detectably. Ras and all of the protein tyrosine kinases analyzed, including the v-erbB product, but none of the nuclear oncoproteins sensitized cells to phorbol ester induction of uPA gene expression. Thus, increased uPA gene expression is not simply a secondary consequence of cell transformation but, rather, is regulated or comodulated by only a subset of oncogene products. Analysis of cells expressing site-directed mutants of pp60v-src showed that the induction of the uPA gene is dependent on protein tyrosine kinase catalytic activity, myristylation, and plasma membrane localization. However, these properties together are not sufficient; an additional feature in the src homology 2 domain is also required. The major sites of serine phosphorylation, serines 12 and 17, and the autophosphorylation site, tyrosine 416, are not essential for uPA gene induction. However, the reduction of uPA mRNA in pp60v-src-transformed cells by 8-bromo cAMP is dependent on tyrosine 416.

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Codony, Carles, Sònia Guil, Concha Caudevilla, Dolors Serra, Guillermina Asins, Adolf Graessmann, Fausto G. Hegardt, and Montse Bach-Elias. "Modulation in vitro of H-ras oncogene expression by trans-splicing." Oncogene 20, no. 28 (June 2001): 3683–94. http://dx.doi.org/10.1038/sj.onc.1204473.

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Pierotti, Marco A., Maria G. Borrello, Italia Bongarzone, Maria R. Cattadori Rosangela Donghi, Piera Mondellini, Catia Traversari, and Giuseppe Della Porta. "Modulation of the human Ha--1 oncogene expression by DNA methylation." European Journal of Cancer and Clinical Oncology 23, no. 11 (November 1987): 1788–89. http://dx.doi.org/10.1016/0277-5379(87)90683-3.

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Taylor, Douglas D., Cicek Gercel-Taylor, and James L. Weese. "Modulation of colon tumor oncogene expression by cancer patient-derived lipids." Journal of Surgical Oncology 63, no. 1 (September 1996): 46–51. http://dx.doi.org/10.1002/(sici)1096-9098(199609)63:1<46::aid-jso8>3.0.co;2-q.

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Perazzona, Bastianella, Yan Wang, and Ralph B. Arlinghaus. "Role of BCR in Down-Modulation of BCR-ABL Oncogenicity in CML." Blood 112, no. 11 (November 16, 2008): 3210. http://dx.doi.org/10.1182/blood.v112.11.3210.3210.

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Abstract Bcr-Abl acquires its transforming ability through its up-regulated Abl tyrosine kinase activity. Bcr is a phosphoprotein with a novel serine/threonine kinase activity encoded by its first exon. Over-expression of BCR in K562 cells produces a phosphoserine form of Bcr and interferes with the oncogenic effects of BCR-ABL in mice (Lin et al., Oncogene 2001). We have recently shown the inhibitory effects of Bcr on Bcr-Abl, in a nude mouse solid tumor model. Expression of BCR/GFP in TonB210 cells used for injection delayed tumor formation and tumors were 50% smaller compared to the TonB210/GFP control. In contrast two point mutants in the BCR kinase domain (Y360F and S354A), not only blocked Bcr’s inhibitory effects but enhanced the oncogenic effects of BCRABL (Perazzona et.al. Oncogene, 2008). Similar Bcr effects were observed in a mouse leukemia model. We are investigating the mechanism of the interaction between Bcr and Bcr-Abl proteins. Using TonB210 cells, in which BCR-ABL expression is controlled by a tetracycline-inducible promoter and Bcr is stably transduced by lentivirus infection, we observed that increasing levels of Bcr-Abl expression increased the levels of the Bcr protein. Treatment of TonB210 cells with imatinib mesylate decreased the levels of Bcr- Abl and surprisingly the Bcr protein as well, indicating that the tyrosine kinase function of Bcr-Abl is required to up-regulate Bcr protein expression. In addition, withdrawal of doxycycline also reduced Bcr-Abl and Bcr protein levels, confirming that Bcr-Abl is required for increased expression of the Bcr protein. In order to examine the levels of Bcr in cells lacking Bcr-Abl, we transduced BCR/GFP with lentivirus infection into BaF3 and 32D cells. Surprisingly, these cell lines expressed extremely low levels of Bcr, despite 90% expression of the GFP marker. Expression of Bcr was restored by overnight treatment with the proteasome inhibitor calpain inhibitor I. Forced expression of Bcr-Abl in BCR- transduced cells restored high expression of Bcr protein, confirming that Bcr- Abl is required for preventing degradation of the Bcr protein. Together these findings indicate that Bcr-Abl up-regulated Bcr expression by interfering with proteasomemediated degradation of the Bcr protein. Additional studies indicated that Bcr increases expression of the myeloid membrane surface marker Mac-1 in Bcr-Abl TonB210 cells, which originated from the mouse pro-B cell BaF3. We propose that Bcr may play a role in generating the myeloid phenotype caused by Bcr-Abl in CML patients and may be an important player in the chronic phase of CML by down-modulating Bcr-Abl.

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Pandey, Pratibha, Fahad Khan, Faisal Abdulrahman Alzahrani, Huda A. Qari, and Mohammad Oves. "A Novel Approach to Unraveling the Apoptotic Potential of Rutin (Bioflavonoid) via Targeting Jab1 in Cervical Cancer Cells." Molecules 26, no. 18 (September 12, 2021): 5529. http://dx.doi.org/10.3390/molecules26185529.

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Rutin has been well recognized for possessing numerous pharmacological and biological activities in several human cancer cells. This research has addressed the inhibitory potential of rutin against the Jab1 oncogene in SiHa cancer cells, which is known to inactivate various tumor suppressor proteins including p53 and p27. Further, the inhibitory efficacy of rutin via Jab1 expression modulation in cervical cancer has not been yet elucidated. Hence, we hypothesized that rutin could exhibit strong inhibitory efficacy against Jab1 and, thereby, induce significant growth arrest in SiHa cancer cells in a dose-dependent manner. In our study, the cytotoxic efficacy of rutin on the proliferation of a cervical cancer cell line (SiHa) was exhibited using MTT and LDH assays. The correlation between rutin and Jab1 mRNA expression was assessed by RT-PCR analysis and the associated events (a mechanism) with this downregulation were then explored via performing ROS assay, DAPI analysis, and expression analysis of apoptosis-associated signaling molecules such as Bax, Bcl-2, and Caspase-3 and -9 using qRT-PCR analysis. Results exhibit that rutin produces anticancer effects via inducing modulation in the expression of oncogenes as well as tumor suppressor genes. Further apoptosis induction, caspase activation, and ROS generation in rutin-treated SiHa cancer cells explain the cascade of events associated with Jab1 downregulation in SiHa cancer cells. Additionally, apoptosis induction was further confirmed by the FITC-Annexin V/PI double staining method. Altogether, our research supports the feasibility of developing rutin as one of the potent drug candidates in cervical cancer management via targeting one such crucial oncogene associated with cervical cancer progression.

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Glaser, Ronald, William P. Lafuse, Robert H. Bonneau, Cathie Atkinson, and Janice K. Kiecolt-Glaser. "Stress-associated modulation of proto-oncogene expression in human peripheral blood leukocytes." Behavioral Neuroscience 107, no. 3 (1993): 525–29. http://dx.doi.org/10.1037/0735-7044.107.3.525.

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Singh, Vijay K., Vaishali I. Parekh, Darren S. Brown, Tzu-Cheg Kao, and Steven R. Mog. "Tocopherol Succinate: Modulation of Antioxidant Enzymes and Oncogene Expression, and Hematopoietic Recovery." International Journal of Radiation Oncology*Biology*Physics 79, no. 2 (February 2011): 571–78. http://dx.doi.org/10.1016/j.ijrobp.2010.08.019.

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Duliban, M., A. Gurgul, T. Szmatola, P. Pawlicki, A. Milon, Z. J. Arent, P. Grzmil, M. Kotula-Balak, and B. Bilinska. "Mouse testicular transcriptome after modulation of non-canonical oestrogen receptor activity." Reproduction, Fertility and Development 32, no. 10 (2020): 903. http://dx.doi.org/10.1071/rd20025.

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The aims of this study were to shed light on the role of G-protein-coupled membrane oestrogen receptor (GPER) and oestrogen-related receptor (ERR) in mouse testis function at the gene expression level, as well as the involvement of GPER and ERR in cellular and molecular processes. Male mice were injected (50µg kg−1,s.c.) with the GPER antagonist G-15, the ERRα inverse agonist XCT790 or the ERRβ/ERRγ agonist DY131. Next-generation sequencing (RNA-Seq) was used to evaluate gene expression. Bioinformatic analysis of read abundance revealed that 50, 86 and 171 transcripts were differentially expressed in the G-15-, XCT790- and DY131-treated groups respectively compared with the control group. Annotated genes and their protein products were categorised regarding their associated biological processes and molecular functions. In the XCT790-treated group, genes involved in immunological processes were upregulated. In the DY131-treated group, genes with increased expression were primarily engaged in protein modification (protein folding and small protein conjugation). In addition, the expression of genes recognised as oncogenes, such as BMI1 proto-oncogene, polycomb ring finger (Bmi1) and nucleophosphin 1 (Npm1), was significantly increased in all experimental groups. This study provides detailed information regarding the genetic changes in the testicular transcriptome of the mouse in response to modulation of non-canonical oestrogen receptor activity.

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L. Gribaldo M. G. Sacco S. Casati I. "MODULATION OF PROTO-ONCOGENE EXPRESSION BY POLYCHLORINATED BIPHENYLS IN 3T3-L1 CELL LINE." Journal of Toxicology and Environmental Health, Part A 55, no. 2 (September 15, 1998): 121–31. http://dx.doi.org/10.1080/009841098158557.

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Radzun, Heinz J., Hans Kreipe, Klaus Heidorn, and Mohammad R. Parwaresch. "Modulation of c-fms Proto-Oncogene Expression in Human Blood Monocytes and Macrophages." Journal of Leukocyte Biology 44, no. 3 (September 1988): 198–204. http://dx.doi.org/10.1002/jlb.44.3.198.

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Scafuro, Marika, Lucia Capasso, Vincenzo Carafa, Lucia Altucci, and Angela Nebbioso. "Gene Transactivation and Transrepression in MYC-Driven Cancers." International Journal of Molecular Sciences 22, no. 7 (March 27, 2021): 3458. http://dx.doi.org/10.3390/ijms22073458.

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MYC is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of MYC gene expression and/or an increase in MYC protein stability. MYC overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.

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Valiuska, Simonas, Alexandra Maria Psaras, Véronique Noé, Tracy A. Brooks, and Carlos J. Ciudad. "Targeting MYC Regulation with Polypurine Reverse Hoogsteen Oligonucleotides." International Journal of Molecular Sciences 24, no. 1 (December 26, 2022): 378. http://dx.doi.org/10.3390/ijms24010378.

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The oncogene MYC has key roles in transcription, proliferation, deregulating cellular energetics, and more. Modulating the expression or function of the MYC protein is a viable therapeutic goal in an array of cancer types, and potential inhibitors of MYC with high specificity and selectivity are of great interest. In cancer cells addicted to their aberrant MYC function, suppression can lead to apoptosis, with minimal effects on non-addicted, non-oncogenic cells, providing a wide therapeutic window for specific and efficacious anti-tumor treatment. Within the promoter of MYC lies a GC-rich, G-quadruplex (G4)-forming region, wherein G4 formation is capable of mediating transcriptional downregulation of MYC. Such GC-rich regions of DNA are prime targets for regulation with Polypurine Reverse Hoogsteen hairpins (PPRHs). The current study designed and examined PPRHs targeting the G4-forming and four other GC-rich regions of DNA within the promoter or intronic regions. Six total PPRHs were designed, examined in cell-free conditions for target engagement and in cells for transcriptional modulation, and correlating cytotoxic activity in pancreatic, prostate, neuroblastoma, colorectal, ovarian, and breast cancer cells. Two lead PPRHs, one targeting the promoter G4 and one targeting Intron 1, were identified with high potential for further development as an innovative approach to both G4 stabilization and MYC modulation.

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Staňková, J., and M. Rola-Pleszczynski. "Leukotriene B4 stimulates c-fos and c-jun gene transcription and AP-1 binding activity in human monocytes." Biochemical Journal 282, no. 3 (March 15, 1992): 625–29. http://dx.doi.org/10.1042/bj2820625.

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We have examined the effect of leukotriene B4 (LTB4), a potent lipid proinflammatory mediator, on the expression of the proto-oncogenes c-jun and c-fos. In addition, we looked at the modulation of nuclear factors binding specifically to the AP-1 element after LTB4 stimulation. LTB4 increased the expression of the c-fos gene in a time- and concentration-dependent manner. The c-jun mRNA, which is constitutively expressed in human peripheral-blood monocytes at relatively high levels, was also slightly augmented by LTB4, although to a much lower extent than c-fos. The kinetics of expression of the two genes were also slightly different, with c-fos mRNA reaching a peak at 15 min after stimulation and c-jun at 30 min. Both messages rapidly declined thereafter. Stability of the c-fos and c-jun mRNA was not affected by LTB4, as assessed after actinomycin D treatment. Nuclear transcription studies in vitro showed that LTB4 increased the transcription of the c-fos gene 7-fold and the c-jun gene 1.4-fold. Resting monocytes contained nuclear factors binding to the AP-1 element, but stimulation of monocytes with LTB4 induced greater AP-1-binding activity of nuclear proteins. These results indicate that LTB4 may regulate the production of different cytokines by modulating the yield and/or the function of transcription factors such as AP-1-binding proto-oncogene products.

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Dewson, Gabrielle, Benedict Anchang, Rosalie Sears, and Daniel F. Liefwalker. "Abstract 825: Evasion of apoptosis in MYC dependent T-ALL through epigenetic control." Cancer Research 82, no. 12_Supplement (June 15, 2022): 825. http://dx.doi.org/10.1158/1538-7445.am2022-825.

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Abstract Cancer is a complex landscape of aberrant cell signaling programs, often initiated by oncogenes. The causal oncogene drives the preponderance of accumulated mutations that enable tumorigenesis. Cancers arising this way can be reliant on the initiating oncogene, a term known as oncogene addiction. The proto-oncogene c-MYC is a transcription factor that regulates much of the genome and is deregulated in many cancers. The transgenic Eµ-tTA/Tet-O-MYC mouse model of T-cell acute lymphoblastic leukemia (T-ALL), allows for modulation of c-MYC expression (ON vs OFF). When c-MYC is expressed, T-ALL progression is observed; and when c-MYC expression is revoked, tumor regression occurs. Using cells and microarray data from this model we employed a nested effects model (NEM) that infers hierarchical relationships anchored to master transcription factors that govern critical aspects of cell biology. We identified a critical node governed by a class of histone demethylases influencing transcriptional availability across the genome. KDM5B/JARID1b is known as a transcriptional repressor, and is downregulated in the T-ALL model when c-MYC is overexpressed. Using CRISPR/Cas9 mediated mutagenesis to disrupt KDM5B expression, we observed a potent reduction in cell death when c-MYC expression is abrogated; suggesting KDM5B mediates cell death responses in T-ALL. KDM5B is downregulated in the primary murine model when c-MYC is overexpressed, and upregulated concordantly with the loss of MYC expression. Human lymphoma cell lines that are sensitive to the bromodomain inhibitor JQ1 show downregulation of c-MYC and KDM5B upregulation. Xenografts of KDM5B knockout cells in NOD-SCIDIL-2Rg-/- (NSG) mice show increased tumor progression and burden, and more aggressive time to relapse after c-MYC expression is revoked. Future studies examining the KDM5B/c-MYC axis and its influence on chromatin architecture are ongoing. These studies aim to demonstrate a novel paradigm in understanding how c-MYC promotes tumor development through repression of a tumor suppressive epigenetic landscape regulated by KDM5B and identify therapeutic options for treating c-MYC-induced T-ALL. Citation Format: Gabrielle Dewson, Benedict Anchang, Rosalie Sears, Daniel F. Liefwalker. Evasion of apoptosis in MYC dependent T-ALL through epigenetic control [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 825.

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Chang, Tsui, Lin, Hou, Feng, and Juang. "Migration and Invasion Enhancer 1 Is an NF-ĸB-Inducing Gene Enhancing the Cell Proliferation and Invasion Ability of Human Prostate Carcinoma Cells In Vitro and In Vivo." Cancers 11, no. 10 (October 2, 2019): 1486. http://dx.doi.org/10.3390/cancers11101486.

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: Migration and invasion enhancer 1 (MIEN1) is a membrane-anchored protein and exists in various cancerous tissues. However, the roles of MIEN1 in prostate cancer have not yet been clearly addressed. We determined the expression, biological functions, and regulatory mechanisms of MIEN1 in the prostate. The results of immunohistochemical analysis indicated that MIEN1 was expressed specifically in epithelial cells and significantly higher in adenocarcinoma as compared to in normal tissues. MIEN1 enhanced in vitro cell proliferation, invasion, and in vivo tumorigenesis. Meanwhile, MIEN1 attenuated cisplatin-induced apoptosis in PC-3 cells. Overexpression of NF-ĸB-inducing kinase (NIK) enhanced MIEN1 expression, while overexpression of NF-ĸB inhibitor α (IĸBα) blocked MIEN1 expression in PC-3 cells. In prostate carcinoma cells, MIEN1 provoked Akt phosphorylation; moreover, MIEN1 downregulated N-myc downstream regulated 1 (NDRG1) but upregulated interleukin-6 (IL-6) gene expression. MK2206, an Akt inhibitor, impeded the modulation of MIEN1 on NDRG1 and IL-6 expressions. Our studies suggest that MIEN1 is an NF-ĸB downstream oncogene in the human prostate. Accordingly, the modulation of Akt signaling in the gene expressions of NDRG1 and IL-6 may account for the functions of MIEN1 in cell proliferation, invasion, and tumorigenesis in prostate carcinoma cells.

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Yu, Joanne L., Rosie Xing, Chloe Milsom, and Janusz Rak. "Modulation of the oncogene-dependent tissue factor expression by kinase suppressor of ras 1." Thrombosis Research 126, no. 1 (July 2010): e6-e10. http://dx.doi.org/10.1016/j.thromres.2010.04.014.

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Liu, Minghui, Kai Yin, Xu Guo, Huijin Feng, Min Yuan, Yanqing Liu, Jianguo Zhang, et al. "Diphthamide Biosynthesis 1 is a Novel Oncogene in Colorectal Cancer Cells and is Regulated by MiR-218-5p." Cellular Physiology and Biochemistry 44, no. 2 (2017): 505–14. http://dx.doi.org/10.1159/000485087.

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Background/Aims: This study focused on the oncogenic role of Diphthamide biosynthesis 1 (DPH1) in colorectal cancer (CRC) cells. Methods: The expression of DPH1 was determined by quantitative RT-PCR analysis and western blotting in CRC tissues. The role of DPH1 in CRC cells was investigated via cell viability and invasion assays under the condition of DPH1 silencing or overexpression. Bioinformatics analysis and luciferase reporter analysis were used to identify the upstream microRNA which might regulate DPH1.The inverse correlation between the microRNA and DPH1 was also detected in CRC cells. Results: We identified an unexpected role for DPH1 as an oncogene in CRC cells. The tumour-suppressive miR-218-5p regulates DPH1 directly and negatively. Loss of miR-218-5p drives the oncogenic role of DPH1 in CRC cells. Conclusion: The modulation of DPH1 by miR-218-5p may be an important regulatory axis during CRCtumourigenesis.

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Liu, Zexuan, Kristin A. Altwegg, Junhao Liu, Susan T. Weintraub, Yidong Chen, Zhao Lai, Gangadhara R. Sareddy, Suryavathi Viswanadhapalli, and Ratna K. Vadlamudi. "Global Genomic and Proteomic Analysis Identified Critical Pathways Modulated by Proto-Oncogene PELP1 in TNBC." Cancers 14, no. 4 (February 13, 2022): 930. http://dx.doi.org/10.3390/cancers14040930.

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The PELP1 oncogene is commonly overexpressed in many cancers, including triple negative breast cancer (TNBC). However, the mechanisms by which PELP1 contributes to TNBC progression are not well understood. To elucidate these mechanisms, we generated CRISPR-Cas9 mediated PELP1 knockout TNBC cell lines, and alterations in the proteome were examined using global data-independent acquisition mass spectrometry (DIA-MS). Further mechanistic studies utilized shRNA knockdown, Western blotting, and RNA-seq approaches. TCGA data sets were utilized for determining the status of PELP1 in TNBC patient tumors and for examining its correlation with ribosomal proteins. Global DIA-MS studies revealed that 127 proteins are upregulated while 220 proteins are downregulated upon PELP1-KO. Bioinformatic analyses suggested that the oncogenic activities of PELP1 involve regulation of expression of ribosomal proteins and ribosomal complexes. RNA-seq studies further suggested PELP1 modulates the functions of transcription factor c-Myc in TNBC. TCGA data confirmed PELP1 has high expression in TNBC patient tumors, and this high expression pattern correlates with c-Myc, a regulator of ribosomal proteins. Collectively, our global approach studies suggest that PELP1 contributes to TNBC progression by modulation of cell cycle, apoptosis, and ribosome biogenesis pathways.

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Reiser, Christian O. A., Martin Marx, Jürgen Hoppe, and Margarete Goppelt-Struebe. "Modulation of Prostaglandin G/H Synthase Expression in Mesangial Cells Transfected by pp60c-srcProto-oncogene." Experimental Cell Research 222, no. 2 (February 1996): 304–11. http://dx.doi.org/10.1006/excr.1996.0039.

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Cristóbal, Ion, Blanca Torrejón, Jaime Rubio, Andrea Santos, Manuel Pedregal, Cristina Caramés, Sandra Zazo, et al. "Deregulation of SET is Associated with Tumor Progression and Predicts Adverse Outcome in Patients with Early-Stage Colorectal Cancer." Journal of Clinical Medicine 8, no. 3 (March 12, 2019): 346. http://dx.doi.org/10.3390/jcm8030346.

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SET nuclear proto-oncogene (SET) deregulation is a novel molecular target in metastatic colorectal cancer (CRC). However, its role in CRC progression and its potential clinical impact in early-stage CRC patients remain unknown. Here, we studied the biological effects of SET on migration using wound-healing and transwell assays, and anchorage-independent cell growth using soft agar colony formation assays after ectopic SET modulation. SET was analyzed by immuno-staining in 231 early-stage CRC patients, and miR-199b expression was quantified by real-time PCR in a set of CRC patients. Interestingly, SET enhances cell migration, markedly affects the colony-forming ability, promotes epithelial to mesenchymal transition, and induces the expression of the MYC proto-oncogene (c-MYC) in CRC cells. SET overexpression was detected in 15.4% of cases and was associated with worse Eastern Cooperative Oncology Group (ECOG) status (p = 0.021) and relapse in stage-II CRC patients (p = 0.008). Moreover, SET overexpression predicted shorter overall survival (p < 0.001) and time to metastasis (p < 0.001), and its prognostic value was particularly evident in elderly patients. MiR-199b downregulation was identified as a molecular mechanism to deregulate SET in patients with localized disease. In conclusion, SET overexpression is a common alteration in early-stage CRC, playing an oncogenic role associated with progression and aggressiveness, and portends a poor outcome. Thus, SET emerges as a novel potential molecular target with clinical impact in early-stage in CRC.

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Smola, Sigrun, Connie Trimble, and Peter L. Stern. "Human papillomavirus-driven immune deviation: challenge and novel opportunity for immunotherapy." Therapeutic Advances in Vaccines 5, no. 3 (June 2017): 69–82. http://dx.doi.org/10.1177/2051013617717914.

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It is now recognized that the immune system can be a key component of restraint and control during the neoplastic process. Human papillomavirus (HPV)-associated cancers of the anogenital tract and oropharynx represent a significant clinical problem but there is a clear opportunity for immune targeting of the viral oncogene expression that drives cancer development. However, high-risk HPV infection of the target epithelium and the expression of the E6/E7 oncogenes can lead to early compromise of the innate immune system (loss of antigen-presenting cells) facilitating viral persistence and increased risk of cancer. In these circumstances, a succession of interacting and self-reinforcing events mediated through modulation of different immune receptors, chemokine and cytokine responses (CCL20; CCL2; CCR2; IL-6; CCR7; IL-12) further promote the generation of an immune suppressive microenvironment [increased levels of Tregs, Th17, myeloid-derived suppressor cells (MDSCs) and PD-L1]. The overexpression of E6/E7 expression also compromises the ability to repair cellular DNA, leading to genomic instability, with the acquisition of genetic changes providing for the selection of advantaged cancer cells including additional strategies for immune escape. Therapeutic vaccines targeting the HPV oncogenes have shown some encouraging success in some recent early-phase clinical trials tested in patients with HPV-associated high-grade anogenital lesions. A significant hurdle to success in more advanced disease will be the local and systemic immune suppressive factors. Interventions targeting the different immunosuppressive components can provide opportunity to release existing or generate new and effective antitumour immunity. Treatments that alter the protumour inflammatory environment including toll-like receptor stimulation, inhibition of IL-6-related pathways, immune-checkpoint inhibition, direct modulation of MDSCs, Tregs and macrophages could all be useful in combination with therapeutic HPV vaccination. Future progress in delivering successful immunotherapy will depend on the configuration of treatment protocols in an insightful and timely combination.

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Harris, Aleishia, Stacie Lambert, Sheri Krams, and Olivia M. Martinez. "Epstein-Barr Virus Latent Membrane Protein 1 Modulates Host MicroRNAs in B Cell Lymphomas. (141.37)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 141.37. http://dx.doi.org/10.4049/jimmunol.182.supp.141.37.

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Abstract Epstein-Barr Virus (EBV) infection is usually benign but immunosuppression can promote post-transplant lymphoproliferative disease (PTLD) and B cell lymphomas in transplant recipients. Latent membrane protein 1 (LMP1) is an important EBV-encoded oncogene that usurps cellular pathways to drive B cell transformation. MicroRNA (miRNA) are tiny, non-coding RNA that regulate cellular gene expression. Since aberrant expression of miRNA has been observed in a variety of malignancies, we hypothesized that modulation of cellular miRNA expression by EBV may play a role in the development of EBV+ B cell lymphomas. Infection of B cell lymphoma lines with EBV significantly modulated expression of miRNA-7, -15b, -221, and -222. Importantly, a similar pattern of microRNA expression was observed in an EBV+ B cell line derived from a patient with PTLD. Activation of a chimeric LMP1 signaling system in EBV negative B lymphoma cell lines also led to induction of miRNA-221 and -222 expression. These mRNA target the cell cycle regulators p27 and p57. Thus, LMP1 can promote cell cycle progression in B cells through miRNA expression. Modulation of miRNA may be a novel mechanism by which EBV drives lymphomagenesis.

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Cavnar, Michael J., Shan Zeng, Teresa S. Kim, Eric C. Sorenson, Lee M. Ocuin, Vinod P. Balachandran, Adrian M. Seifert, et al. "KIT oncogene inhibition drives intratumoral macrophage M2 polarization." Journal of Experimental Medicine 210, no. 13 (December 9, 2013): 2873–86. http://dx.doi.org/10.1084/jem.20130875.

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Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers.

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de Barrios, Oriol, Ainara Meler, and Maribel Parra. "MYC’s Fine Line Between B Cell Development and Malignancy." Cells 9, no. 2 (February 24, 2020): 523. http://dx.doi.org/10.3390/cells9020523.

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The transcription factor MYC is transiently expressed during B lymphocyte development, and its correct modulation is essential in defined developmental transitions. Although temporary downregulation of MYC is essential at specific points, basal levels of expression are maintained, and its protein levels are not completely silenced until the B cell becomes fully differentiated into a plasma cell or a memory B cell. MYC has been described as a proto-oncogene that is closely involved in many cancers, including leukemia and lymphoma. Aberrant expression of MYC protein in these hematological malignancies results in an uncontrolled rate of proliferation and, thereby, a blockade of the differentiation process. MYC is not activated by mutations in the coding sequence, and, as reviewed here, its overexpression in leukemia and lymphoma is mainly caused by gene amplification, chromosomal translocations, and aberrant regulation of its transcription. This review provides a thorough overview of the role of MYC in the developmental steps of B cells, and of how it performs its essential function in an oncogenic context, highlighting the importance of appropriate MYC regulation circuitry.

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Annunziata, Christina M., Lidia Hernandez, R. Eric Davis, Adriana Zingone, Laurence Lamy, Lloyd T. Lam, Elaine M. Hurt, Arthur L. Shaffer, W. Michael Kuehl, and Louis M. Staudt. "A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression." Blood 117, no. 8 (February 24, 2011): 2396–404. http://dx.doi.org/10.1182/blood-2010-04-278788.

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Abstract Modulating aberrant transcription of oncogenes is a relatively unexplored opportunity in cancer therapeutics. In approximately 10% of multiple myelomas, the initiating oncogenic event is translocation of musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a transcriptional activator of key target genes, including cyclinD2. Our prior work showed that MAF is up-regulated in an additional 30% of multiple myeloma cases. The present study describes a common mechanism inducing MAF transcription in both instances. The second mode of MAF transcription occurred in myelomas with multiple myeloma SET domain (MMSET) translocation. MMSET knockdown decreased MAF transcription and cell viability. A small-molecule screen found an inhibitor of mitogen-activated protein kinase kinase (MEK), which activates extracellular signal-regulated kinase (ERK)-MAP kinases, reduced MAF mRNA in cells representing MMSET or MAF subgroups. ERK activates transcription of FOS, part of the AP-1 transcription factor. By chromatin immunoprecipitation, FOS bound the MAF promoter, and MEK inhibition decreased this interaction. MEK inhibition selectively induced apoptosis in MAF-expressing myelomas, and FOS inactivation was similarly toxic. Reexpression of MAF rescued cells from death induced by MMSET depletion, MEK inhibition, or FOS inactivation. The data presented herein demonstrate that the MEK-ERK pathway regulates MAF transcription, providing molecular rationale for clinical evaluation of MEK inhibitors in MAF-expressing myeloma.

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Kozono, David, Jie Li, Masayuki Nitta, Oltea Sampetrean, David Gonda, Deepa S. Kushwaha, Dmitry Merzon, et al. "Dynamic epigenetic regulation of glioblastoma tumorigenicity through LSD1 modulation of MYC expression." Proceedings of the National Academy of Sciences 112, no. 30 (July 9, 2015): E4055—E4064. http://dx.doi.org/10.1073/pnas.1501967112.

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The available evidence suggests that the lethality of glioblastoma is driven by small subpopulations of cells that self-renew and exhibit tumorigenicity. It remains unclear whether tumorigenicity exists as a static property of a few cells or as a dynamically acquired property. We used tumor-sphere and xenograft formation as assays for tumorigenicity and examined subclones isolated from established and primary glioblastoma lines. Our results indicate that glioblastoma tumorigenicity is largely deterministic, yet the property can be acquired spontaneously at low frequencies. Further, these dynamic transitions are governed by epigenetic reprogramming through the lysine-specific demethylase 1 (LSD1). LSD depletion increases trimethylation of histone 3 lysine 4 at the avian myelocytomatosis viral oncogene homolog (MYC) locus, which elevates MYC expression. MYC, in turn, regulates oligodendrocyte lineage transcription factor 2 (OLIG2), SRY (sex determining region Y)-box 2 (SOX2), and POU class 3 homeobox 2 (POU3F2), a core set of transcription factors required for reprogramming glioblastoma cells into stem-like states. Our model suggests epigenetic regulation of key transcription factors governs transitions between tumorigenic states and provides a framework for glioblastoma therapeutic development.

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D’Aria, Federica, Bruno Pagano, Luigi Petraccone, and Concetta Giancola. "KRAS Promoter G-Quadruplexes from Sequences of Different Length: A Physicochemical Study." International Journal of Molecular Sciences 22, no. 1 (January 5, 2021): 448. http://dx.doi.org/10.3390/ijms22010448.

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DNA G-quadruplexes (G4s) form in relevant genomic regions and intervene in several biological processes, including the modulation of oncogenes expression, and are potential anticancer drug targets. The human KRAS proto-oncogene promoter region contains guanine-rich sequences able to fold into G4 structures. Here, by using circular dichroism and differential scanning calorimetry as complementary physicochemical methodologies, we compared the thermodynamic stability of the G4s formed by a shorter and a longer version of the KRAS promoter sequence, namely 5′-AGGGCGGTGTGGGAATAGGGAA-3′ (KRAS 22RT) and 5′-AGGGCGGTGTGGGAAGAGGGAAGAGGGGGAGG-3′ (KRAS 32R). Our results show that the unfolding mechanism of KRAS 32R is more complex than that of KRAS 22RT. The different thermodynamic stability is discussed based on the recently determined NMR structures. The binding properties of TMPyP4 and BRACO-19, two well-known G4-targeting anticancer compounds, to the KRAS G4s were also investigated. The present physicochemical study aims to help in choosing the best G4 target for potential anticancer drugs.

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Marzi, Matteo J., Eleonora M. R. Puggioni, Valentina Dall'Olio, Gabriele Bucci, Loris Bernard, Fabrizio Bianchi, Marco Crescenzi, Pier Paolo Di Fiore, and Francesco Nicassio. "Differentiation-associated microRNAs antagonize the Rb–E2F pathway to restrict proliferation." Journal of Cell Biology 199, no. 1 (October 1, 2012): 77–95. http://dx.doi.org/10.1083/jcb.201206033.

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The cancer-associated loss of microRNA (miRNA) expression leads to a proliferative advantage and aggressive behavior through largely unknown mechanisms. Here, we exploit a model system that recapitulates physiological terminal differentiation and its reversal upon oncogene expression to analyze coordinated mRNA/miRNA responses. The cell cycle reentry of myotubes, forced by the E1A oncogene, was associated with a pattern of mRNA/miRNA modulation that was largely reciprocal to that induced during the differentiation of myoblasts into myotubes. The E1A-induced mRNA response was preponderantly Retinoblastoma protein (Rb)-dependent. Conversely, the miRNA response was mostly Rb-independent and exerted through tissue-specific factors and Myc. A subset of these miRNAs (miR-1, miR-34, miR-22, miR-365, miR-29, miR-145, and Let-7) was shown to coordinately target Rb-dependent cell cycle and DNA replication mRNAs. Thus, a dual level of regulation—transcriptional regulation via Rb–E2F and posttranscriptional regulation via miRNAs—confers robustness to cell cycle control and provides a molecular basis to understand the role of miRNA subversion in cancer.

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Versteeg, R., L. T. Peltenburg, A. C. Plomp, and P. I. Schrier. "High expression of the c-myc oncogene renders melanoma cells prone to lysis by natural killer cells." Journal of Immunology 143, no. 12 (December 15, 1989): 4331–37. http://dx.doi.org/10.4049/jimmunol.143.12.4331.

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Abstract NK cells kill a wide variety of tumor cells, but usually leave normal cells intact. It was earlier reported that low class I HLA expression can be one of the factors that render target cells relatively susceptible to NK lysis. In this contribution, we show that in human melanomas the class I HLA expression is down-modulated by high expression of transfected c-myc oncogenes. The extent of down-modulation depended on the level of c-myc expression in a dose-dependent way. Taken together, these data suggested to us that one of the results of high c-myc expression could be the induction of a NK susceptible phenotype in melanoma cells. Therefore, we analyzed the effect of c-myc on NK susceptibility. We have found that high expression of transfected c-myc genes indeed converts the melanoma cell lines from poor into good targets for NK cells. IFN-gamma was used to restore the class I HLA expression of the c-myc transfectants, and the resulting cells showed a decreased NK susceptibility. These results suggest the possibility that the c-myc-induced NK susceptibility is mediated by the reduction of class I HLA expression.

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Santos, G. F., G. K. Scott, W. M. Lee, E. Liu, and C. Benz. "Estrogen-induced post-transcriptional modulation of c-myc proto-oncogene expression in human breast cancer cells." Journal of Biological Chemistry 263, no. 20 (July 1988): 9565–68. http://dx.doi.org/10.1016/s0021-9258(19)81551-x.

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Peterson, D. A., B. Kelly, J. Butterfield, J. Ashley, R. Peterson, and J. M. Gerrard. "Phosphorylation of tyrosine enhances its electron transfer capability: A model of redox modulation as oncogene expression?" Medical Hypotheses 26, no. 4 (August 1988): 271–73. http://dx.doi.org/10.1016/0306-9877(88)90133-8.

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Roth, Jack A. "Modulation of oncogene and tumor-suppressor gene expression: A novel strategy for cancer prevention and treatment." Annals of Surgical Oncology 1, no. 1 (January 1994): 79–86. http://dx.doi.org/10.1007/bf02303545.

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Wee, YongKiat, Yining Liu, and Min Zhao. "Identification of consistent post-translational regulatory triplets related to oncogenic and tumour suppressive modulators in childhood acute lymphoblastic leukemia." PeerJ 9 (July 14, 2021): e11803. http://dx.doi.org/10.7717/peerj.11803.

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Background Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. It can be caused by mutations that turn on oncogenes or turn off tumour suppressor genes. For instance, changes in certain genes including Rb and p53 are common in ALL cells. Oncogenes and TSGs may serve as a modulator gene to regulate the gene expression level via their respective target genes. To investigate the regulatory relationship between oncogenes, tumour suppressor genes and transcription factors at the post translational level in childhood ALL, we performed an integrative network analysis on the gene regulation in the post-translational level for childhood ALL based on many publicly available cancer gene expression data including TARGET and GEO database. Methods We collected 259 childhood ALL-related genes from the latest online leukemia database, Leukemia Gene Literature Database. These 259 genes were selected from a comprehensive systematic literature with experimental evidences. The identified and curated genes were also associated with patient survival cases and we incorporated this pediatric ALL-related gene list into our analysis. We extracted the known human TFs from the TRRUST database. Among 259 childhood ALL-related genes, 101 unique regulators were mapped to the list of oncogene and tumour suppressor genes (TSGs) from the ONGene and the TSGene databases, and these included 74 TSGs, 62 oncogenes and 46 TF genes. Results The resulted regulation was presented as a hierarchical regulatory network with transcription factors (TFs) as intermediate regulators connecting the top modulators (oncogene and TSGs) to the common target genes. Cross-validation was applied to the results from the TARGET dataset by identifying the consistent regulatory motifs based on three independent ALL expression datasets. A three-layer regulatory network of consistent positive modulators in childhood ALL was constructed in which 74 modulators (40 oncogenes, 34 TSGs) are considered as the most important regulators. The middle layer and the bottom layer contain 34 TFs and 176 target genes, respectively. Oncogenes mostly participated in positive regulation of gene expression and the transcription process of RNA II polymerase, while TSGs were mainly involved in the negative regulation of gene expression. In addition, the oncogene-specific targets were enriched with regulators of the MAPK cascade while tumour suppressor-specific targets were associated with cell death. Conclusion The results revealed that oncogenes and TSGs possess a different functional regulatory pattern with regard to not only their biological functions but also their specific target genes in childhood ALL cancer progression. Taken together, our findings could contribute to a better understanding of the important regulatory mechanisms and this method could be used to analyse the targeted genes at the post-translational level in childhood ALL through integrative network analysis.

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Sekeris, E. "Hormonal steroids act as tumour promoters by modulating oncogene expression." Journal of Cancer Research and Clinical Oncology 117, no. 2 (March 1991): 96–101. http://dx.doi.org/10.1007/bf01613131.

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Kelvin, David J., Terry P. Yamaguchi, Gilles Simard, Helen H. Tai, Andrew I. Sue-A-Quan, Greg T. Sue-A-Quan, and Joe A. Connolly. "A model for the modulation of muscle cell determination and differentiation by growth factors." Biochemistry and Cell Biology 67, no. 9 (September 1, 1989): 575–80. http://dx.doi.org/10.1139/o89-089.

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In an adult organism three principal types of muscle tissue can be found: skeletal, smooth, and cardiac. While each display subtle differences, for the most part they express a common set of genes that are representative of differentiated muscle. Several in vitro muscle cell lines have provided clues as to how the developmental programs of muscle cell proliferation, determination, and differentiation are controlled. In this paper we will explore recent advances in our understanding of how growth factors, acting through specific signal transduction pathways, control muscle gene expression. The transcription of muscle genes is controlled by specific cis-acting regulatory sequences. We will discuss how growth factors may exert their effects on muscle genes by modulating the expression of nuclear DNA-binding proteins that directly regulate muscle gene expression.Key words: determination, myogenesis, oncogene, fibroblast growth factor, myoD1.

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Senapedis, William, Elmer Figueroa, Kayleigh Gallagher, Jeremiah Farelli, Robert Lyng, Charles O'Donnell, Joseph Newman, and Thomas McCauley. "Abstract 2629: Epigenetic modulation of the MYC oncogene as a potential novel therapy for HCC." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2629. http://dx.doi.org/10.1158/1538-7445.am2022-2629.

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Abstract Hepatocellular carcinoma (HCC), the fourth leading cause of cancer deaths, represents an unmet medical need with few therapeutic options. Sorafenib has been used as a systemic therapy for HCC for >10 years but patients frequently develop resistance with oncogenic c-MYC (MYC) identified as a correlating prognostic factor. MYC over-expression is associated with aggressive disease in up to ~70% of HCC. While MYC represents an attractive therapeutic target, it has historically been considered undruggable, largely because it lacks a structured binding pocket and its expression is tightly autoregulated. The MYC gene and its regulatory elements are part of an insulated genomic domain (IGD), a chromatin looping region anchored by CTCF. Here we describe our approach to specifically modulate levels of MYC expression by utilizing targeted mRNA-encoded proteins, Omega Epigenomic Controllers (OECs), to mediate epigenetic regulation while potentially overcoming MYC autoregulation. For screening, putative OECs were directed to 2 loci on the MYC IGD. Identified target loci were used to design optimized OECs, including development candidate OTX-2002. We characterized OTX-2002 in HCC cell lines, measuring MYC mRNA and cell viability. OTX-2002 was tested for durable epigenetic and transcriptomic changes. Changes in MYC protein levels and pathway signaling were measured using proteomic methods. Finally, we analyzed activity of OTX-2002 in in vivo subcutaneous (subQ) and orthotopic HCC models by assessing tumor volume, tumor-associated bioluminescence (BLI) and immunohistochemistry (IHC). OTX-2002 was effective at decreasing MYC mRNA, protein and cell viability in HCC cells while sparing normal cells. In HCC cells, OTX-2002 median EC50 of inhibition is <0.001 ng/mL for MYC mRNA and 120 ng/mL for cell viability. Importantly, the effects of OTX-2002 persisted for >2 weeks, providing durable MYC mRNA repression. IV delivery of OTX-2002 in lipid nanoparticles at 3 and 6 mg/kg Q5D in a Hep 3B subQ model in athymic nude mice demonstrated statistically significant tumor growth inhibition (TGI) of 54% and 63%, respectively, by Day 23 compared to negative control. OTX-2002-treated mice did not have a significant decrease in bodyweight (BW) compared to negative control or sorafenib-treated mice. IHC of OTX-2002 and control treated tumors showed significant down-regulation of MYC with reduced proliferation (Ki67) and increased apoptosis (Caspase 3). In a Hep 3B orthotopic model 3 mg/kg OTX-2002 Q5D showed a comparable reduction of BLI to sorafenib at 50 mg/kg QD without the reduction in BW. Our findings identify a therapeutic in vitro and in vivo approach that enables transcriptional modulation of the MYC oncogene through precise epigenomic programming of the IGD in which it resides. Targeting MYC in this manner may represent a potentially differentiated and viable approach to the treatment of HCC in humans. Citation Format: William Senapedis, Elmer Figueroa, Kayleigh Gallagher, Jeremiah Farelli, Robert Lyng, Charles O'Donnell, Joseph Newman, Thomas McCauley. Epigenetic modulation of the MYC oncogene as a potential novel therapy for HCC [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 2629.

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Freire, Natália Hogetop, Alice Laschuk Herlinger, Julia Vanini, Matheus Dalmolin, Marcelo A. C. Fernandes, Carolina Nör, Vijay Ramaswamy, et al. "Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres." Cells 14, no. 2 (January 7, 2025): 72. https://doi.org/10.3390/cells14020072.

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Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced MYC while increasing TP53 expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes TUBB3 and ENO2. The expression of stemness genes SOX2, NES, and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53. Among the genes regulated by VPA, the stemness regulators MYC and NES showed an association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in the modulation of stemness, neuronal differentiation, and the expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in the expression of MYC and an increase in TP53.

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Chen, Ji-Long, Andre Limnander, and Paul B. Rothman. "Pim-1 and Pim-2 kinases are required for efficient pre–B-cell transformation by v-Abl oncogene." Blood 111, no. 3 (February 1, 2008): 1677–85. http://dx.doi.org/10.1182/blood-2007-04-083808.

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Abstract The precise mechanisms by which Abl oncogenes transform hematopoietic cells are unknown. We have examined the role of Pim kinases in v-Abl–mediated transformation. In v-Abl transformants, expression of Pim-1 and Pim-2, but not Pim-3, is dependent on Abl kinase activity. Transformation assays demonstrate that v-Abl cannot efficiently transform bone marrow cells derived from Pim-1−/−/Pim-2−/− mice. Ectopic expression of either Pim-1 or Pim-2 in Pim-1−/−/Pim-2−/− cells restores transformation by v-Abl, strongly suggesting that either Pim-1 or Pim-2 is required for v-Abl–mediated tumorigenesis. Interestingly, the combined deficiency of Pim-1, Pim-2, and Suppressor of Cytokine Signalling (SOCS)-1 resulted in partial restoration of v-Abl transformation efficiency. In addition, Pim kinases are involved in modification of SOCS-1 and in regulating SOCS-1 protein levels in v-Abl–transformed cells. Furthermore, Pim kinases regulate the proapoptotic proteins Bcl-XS and BAD. Pim kinases inhibit the expression of Bcl-XS. Pim deficiency decreases the phosphorylation levels of BAD, whereas ectopic expression of Pim-1 increases the amount of phospho-BAD. This correlates with an increased protection from apoptosis in Abl transformants expressing Pim kinases. Together, these data suggest that Pim kinases play a key role in the v-Abl transformation, possibly via participating in modulation of SOCS-1 and via regulating the apoptotic signaling.

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Lian, Jane B., and Gary S. Stein. "Concepts of Osteoblast Growth and Differentiation: Basis for Modulation of Bone Cell Development and Tissue Formation." Critical Reviews in Oral Biology & Medicine 3, no. 3 (April 1992): 269–305. http://dx.doi.org/10.1177/10454411920030030501.

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The combined application of molecular, biochemical, histochemical, and ultrastructural approaches has defined a temporal sequence of gene expression associated with development of the bone cell phenotype in primary osteoblast cultures. The peak levels of expressed genes reflect a developmental sequence of bone cell differentiation characterized by three principal periods: proliferation, extracellular matrix maturation and mineralization, and two restriction points to which the cells can progress but cannot pass without further signals. The regulation of cell growth and bone-specific gene expression has been examined during this developmental sequence and is discussed within the context of several unique concepts. These are (1) that oncogene expression in proliferating osteoblasts contributes to the suppression of genes expressed postproliferatively, (2) that hormone modulation of a gene is dependent upon the maturational state of the osteoblast, and (3) that chromatin structure and the presence of nucleosomes contribute to three-dimensional organization of gene promoters that support synergistic and/or antagonistic activities of physiologic mediators of bone cell growth and differentiation.

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Moharram, Sausan A., Julhash U. Kazi, and Lars Rönnstrand. "Loss of Src-like Adaptor Protein 2 Expression Increases the Transforming Potential of Oncogenic FLT3-ITD." Blood 128, no. 22 (December 2, 2016): 5106. http://dx.doi.org/10.1182/blood.v128.22.5106.5106.

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Abstract The receptor tyrosine kinase FLT3 is found to be a mutated oncogene in hematological malignancies including acute myeloid leukemia (AML). FLT3 inhibitors in combination with chemotherapy display promising results in a clinical setting, but patients relapse after short-term treatment due to the development of resistant disease. Therefore, targeting signaling proteins downstream of FLT3 can be an alternative approach for the treatment of patients carrying mutant FLT3. Activated FLT3 is constitutively phosphorylated on several tyrosine residues. These tyrosine residues facilitate association of SH2 domain-containing signaling proteins. By using a panel of SH2 domain-containing proteins we identified SLAP2 as a potent interaction partner of FLT3. The interaction in between FLT3 and SLAP2 occurs when FLT3 is activated and an intact SH2 domain of SLAP2 is required for the interaction. SLAP2 associates with FLT3 mainly through its SRC binding sites and expression of SLAP2 inhibited oncogenic FLT3-ITD-mediated cell proliferation and colony formation in vitro, and tumor formation in vivo. By analysis of patient expression data, we found that loss of SLAP2 expression correlates with poor prognosis of AML patients carrying FLT3-ITD. SLAP2 inhibits FLT3-mediated downstream signaling such as activation of AKT, ERK, p38 and STAT5. Inhibition is partially mediated through ubiquitination-mediated degradation of FLT3. Taken together our current study demonstrates that SLAP2 is an important regulator of FLT3-mediated oncogenic signaling and thus modulation of the SLAP2 expression levels can be an alternative approach for the treatment of FLT3-ITD positive malignancies. Disclosures No relevant conflicts of interest to declare.

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Nakayama, J., and K. Urabe. "064 Expression of oncogene c-fos in neurofibroma cells: Modulation by growth factor and vitamin D3 analogue." Journal of Dermatological Science 15, no. 2 (August 1997): 113. http://dx.doi.org/10.1016/s0923-1811(97)81767-7.

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Kramer, Robert, Robert Arceci, Thomas K. Weber, Barry Morse, Heather Simpson, Glenn D. Steele, and Ian C. Summerhayes. "Modulation of MDR-1 expression by a H-ras oncogene in a human colon carcinoma cell line." International Journal of Cancer 54, no. 2 (May 8, 1993): 275–81. http://dx.doi.org/10.1002/ijc.2910540219.

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Journal articles on the topic 'Modulation of oncogene expression'

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