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Gene Review

Myc  -  myelocytomatosis oncogene

Rattus norvegicus

Synonyms: Myc proto-oncogene protein, Proto-oncogene c-Myc, RNCMYC, Transcription factor p64, c-myc, ...
 
 
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Disease relevance of Myc

  • Nucleotide sequence analysis of the mouse AM promoter reveals the presence of consensus CAAT and TATA boxes as well as an initiator element (INR) with significant sequence similarity to the INR responsible for Myc-mediated repression of the adenovirus major late promoter (AdMLP) [1].
  • The expression of c-Myc mRNA is rapidly induced by nerve growth factor (NGF) and epidermal growth factor (EGF) in PC-12 pheochromocytoma cells [2].
  • We also analyzed the effects of Myc and Max ectopic expression on the clonogenic growth of the rat hepatoma cells [3].
  • We have found that hyperglycemia induces the expression of the basic helix-loop-helix transcription factor c-Myc in islets in several different diabetic models [4].
  • The results suggest nonredundant roles for mad genes in hepatocyte proliferation and point to c-Myc as a putative target for anticancer therapy of liver cancer [3].
 

Psychiatry related information on Myc

  • The present results provide additional support for the view that NF-kappaB activation contributes to c-Myc and p53 induction and subsequent apoptosis in an excitotoxic model of Huntington's disease [5].
 

High impact information on Myc

  • Induction of apoptosis in fibroblasts by c-myc protein [6].
  • Although Rat-1 fibroblasts expressing c-myc constitutively are unable to arrest growth in low serum, their numbers do not increase in culture because of substantial cell death [6].
  • Finally, we demonstrate that deregulated c-myc expression induces apoptosis in cells growth arrested by a variety of means and at various points in the cell cycle [6].
  • Moreover, cells with higher levels of c-myc protein are more prone to cell death upon serum deprivation [6].
  • Regions of the c-myc protein required for induction of apoptosis overlap with regions necessary for cotransformation, autoregulation, and inhibition of differentiation, suggesting that the apoptotic function of c-myc protein is related to its other functions [6].
 

Chemical compound and disease context of Myc

  • Because c-Myc regulates the pRb-E2F pathway, we evaluated cell cycle gene expression in neoplastic nodules and hepatocellular carcinomas (HCCs), induced by initiation/selection (IS) protocols 40 and 70 weeks after diethylnitrosamine treatment, in susceptible Fisher 344 (F344) rats, and resistant Wistar and Brown Norway (BN) rats [7].
  • Because mithramycin has been shown to be well tolerated by humans and to effectively inhibit transcription of c-myc in proliferating human cells, this agent may be useful in the prevention of coronary restenosis [8].
  • However, although both EVAc and Pluronic release of c-myb antisense oligonucleotide sequences inhibited intimal hyperplasia 2 weeks after injury, only the more prolonged EVAc matrix release of antisense oligonucleotide to c-myc was effective [9].
  • On the contrary, the hyperplasia induced by cyproterone acetate and nafenopin, which is characterized by a lack of increase in the expression of c-fos and c-jun, was also not associated with an increased c-myc expression [10].
  • The relationship between expression of nucleoside diphosphate kinase (NDP kinase)/nm23, c-Ha-ras, and c-myc genes and metastatic potential was assessed in rat-transplantable osteosarcoma lines, derived from spontaneous and chemical carcinogen (4-hydroxyamino quinoline 1-oxide)-induced osteosarcomas in Fischer 344/NS1c rats [11].
 

Biological context of Myc

 

Anatomical context of Myc

 

Associations of Myc with chemical compounds

  • The aim of our study was to evaluate the effects of c-myc antisense (AS) phosphorothioate oligodeoxynucleotides (ODNs) in the remodelling process induced by surgical carotid arteriotomy on an experimental rat model [17].
  • In contrast, depletion of cellular polyamines by inhibiting ODC enzyme activity with alpha-difluoromethylornithine decreased c-Myc, but increased p21Cip1 transcription [18].
  • A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism [19].
  • We show here that in Rat1 cells expressing an exogenous c-myc allele, distinct apoptotic pathways can be inhibited by Bcl-2 or Bcl-acta yet be distinguished by their sensitivity to Bcl-cb5 as either susceptible (serum withdrawal, taxol, and ceramide) or refractory (etoposide and doxorubicin) [20].
  • Analysis of Rat1 c-myc null cells shows these same death stimuli induce apoptosis with characteristic features of nuclear condensation, membrane blebbing, poly (ADP-ribose) polymerase cleavage, and DNA fragmentation; however, this Myc-independent apoptosis is not inhibited by Bcl-2 [20].
 

Physical interactions of Myc

  • Max is a basic-helix-loop-helix-leucine zipper protein capable of forming sequence-specific DNA binding complexes with Myc proteins [21].
  • A conditionally active chimeric form of the c-Myc protein fused to the ligand-binding domain of the estrogen receptor (MycER) was expressed in PC12 cells [13].
  • When O-2A/c-myc cells underwent terminal differentiation APprog complexes were lost and conventional AP-1 DNA-binding activity became evident, particularly in astrocytes [22].
  • Moreover, as the G0-G1 transition progresses, Id2 and HDAC again bind the c-myc promoter concomitantly with the repression of this gene [23].
  • Using chromatin immunoprecipitation, we show that c-Myc binds to the proximal promoter of the PDGFRB gene in proliferating rat fibroblasts [24].
 

Enzymatic interactions of Myc

  • RESULTS: In cardiac myocyte Ang II increased p44/p42 MAPK activity and phosphorylated protein content by 140 % and 699 %, and also increased [3H]leucine incorporation and cell diameter by 40 % and 27 %. c-fos and c-myc mRNAs were induced significantly after exposure to Ang II [25].
 

Regulatory relationships of Myc

 

Other interactions of Myc

  • It sharply increased in all tissues 4 hours after AMPH treatment (10 mg/kg), and declined to basal levels at 8 to 12 hours in liver and N12, but remained high up to 18 hours in N30 and HCC. c-myc, Tgf-alpha, p53, and Bcl-X(S) messenger RNA (mRNA) levels were higher, and Bcl-2 mRNA was lower in N12 and/or N30 and HCC than in normal liver [29].
  • Myc drives apoptosis in PC12 cells in the absence of Max [13].
  • The Adrenomedullin gene is a target for negative regulation by the Myc transcription complex [1].
  • The expression of c-myc mRNA was greatly enhanced by consumption of the protein-free diet or by starvation, whereas the IGF-1 mRNA levels were reduced markedly by consumption of the zein diet or the protein-free diet or by starvation [30].
  • A modest reduction in c-myc expression has minimal effects on cell growth and apoptosis but dramatically reduces susceptibility to Ras and Raf transformation [31].
 

Analytical, diagnostic and therapeutic context of Myc

References

  1. The Adrenomedullin gene is a target for negative regulation by the Myc transcription complex. Wang, X., Peters, M.A., Utama, F.E., Wang, Y., Taparowsky, E.J. Mol. Endocrinol. (1999) [Pubmed]
  2. c-Myc does not require max for transcriptional activity in PC-12 cells. Ribon, V., Leff, T., Saltiel, A.R. Mol. Cell. Neurosci. (1994) [Pubmed]
  3. Kinetics of myc-max-mad gene expression during hepatocyte proliferation in vivo: Differential regulation of mad family and stress-mediated induction of c-myc. Mauleon, I., Lombard, M.N., Muñoz-Alonso, M.J., Cañelles, M., Leon, J. Mol. Carcinog. (2004) [Pubmed]
  4. Induction of c-Myc expression suppresses insulin gene transcription by inhibiting NeuroD/BETA2-mediated transcriptional activation. Kaneto, H., Sharma, A., Suzuma, K., Laybutt, D.R., Xu, G., Bonner-Weir, S., Weir, G.C. J. Biol. Chem. (2002) [Pubmed]
  5. Kainic acid-induced apoptosis in rat striatum is associated with nuclear factor-kappaB activation. Nakai, M., Qin, Z.H., Chen, J.F., Wang, Y., Chase, T.N. J. Neurochem. (2000) [Pubmed]
  6. Induction of apoptosis in fibroblasts by c-myc protein. Evan, G.I., Wyllie, A.H., Gilbert, C.S., Littlewood, T.D., Land, H., Brooks, M., Waters, C.M., Penn, L.Z., Hancock, D.C. Cell (1992) [Pubmed]
  7. Cell cycle deregulation in liver lesions of rats with and without genetic predisposition to hepatocarcinogenesis. Pascale, R.M., Simile, M.M., De Miglio, M.R., Muroni, M.R., Calvisi, D.F., Asara, G., Casabona, D., Frau, M., Seddaiu, M.A., Feo, F. Hepatology (2002) [Pubmed]
  8. Mithramycin inhibits myointimal proliferation after balloon injury of the rat carotid artery in vivo. Chen, S.J., Chen, Y.F., Miller, D.M., Li, H., Oparil, S. Circulation (1994) [Pubmed]
  9. c-myc in vasculoproliferative disease. Edelman, E.R., Simons, M., Sirois, M.G., Rosenberg, R.D. Circ. Res. (1995) [Pubmed]
  10. Differences in the steady-state levels of c-fos, c-jun and c-myc messenger RNA during mitogen-induced liver growth and compensatory regeneration. Coni, P., Simbula, G., de Prati, A.C., Menegazzi, M., Suzuki, H., Sarma, D.S., Ledda-Columbano, G.M., Columbano, A. Hepatology (1993) [Pubmed]
  11. Increased expression of nucleoside diphosphate kinase/nm23 and c-Ha-ras mRNA is associated with spontaneous lung metastasis in rat-transplantable osteosarcomas. Honoki, K., Tsutsumi, M., Miyauchi, Y., Mii, Y., Tsujiuchi, T., Morishita, T., Miura, S., Aoki, M., Kobayashi, E., Tamai, S. Cancer Res. (1993) [Pubmed]
  12. Myc influences global chromatin structure. Knoepfler, P.S., Zhang, X.Y., Cheng, P.F., Gafken, P.R., McMahon, S.B., Eisenman, R.N. EMBO J. (2006) [Pubmed]
  13. Myc drives apoptosis in PC12 cells in the absence of Max. Wert, M., Kennedy, S., Palfrey, H.C., Hay, N. Oncogene (2001) [Pubmed]
  14. Induction of max by adrenomedullin and calcitonin gene-related peptide antagonizes endothelial apoptosis. Shichiri, M., Kato, H., Doi, M., Marumo, F., Hirata, Y. Mol. Endocrinol. (1999) [Pubmed]
  15. Repression of Myc-Ras cotransformation by Mad is mediated by multiple protein-protein interactions. Koskinen, P.J., Ayer, D.E., Eisenman, R.N. Cell Growth Differ. (1995) [Pubmed]
  16. Expression of c-Fos and c-Myc and deposition of beta-APP in neurons in the adult rat brain as a result of exposure to short-lasting impulse noise. Säljö, A., Bao, F., Shi, J., Hamberger, A., Hansson, H.A., Haglid, K.G. J. Neurotrauma (2002) [Pubmed]
  17. Rat carotid arteriotomy: c-myc is involved in negative remodelling and apoptosis. De Feo, M., Forte, A., Onorati, F., Renzulli, A., Cipollaro, M., Cotrufo, M., Rossi, F., Cascino, A. Journal of cardiovascular medicine (Hagerstown, Md.) (2006) [Pubmed]
  18. Polyamine-modulated c-Myc expression in normal intestinal epithelial cells regulates p21Cip1 transcription through a proximal promoter region. Liu, L., Guo, X., Rao, J.N., Zou, T., Marasa, B.S., Chen, J., Greenspon, J., Casero, R.A., Wang, J.Y. Biochem. J. (2006) [Pubmed]
  19. A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism. Nikiforov, M.A., Chandriani, S., O'Connell, B., Petrenko, O., Kotenko, I., Beavis, A., Sedivy, J.M., Cole, M.D. Mol. Cell. Biol. (2002) [Pubmed]
  20. Myc potentiates apoptosis by stimulating Bax activity at the mitochondria. Soucie, E.L., Annis, M.G., Sedivy, J., Filmus, J., Leber, B., Andrews, D.W., Penn, L.Z. Mol. Cell. Biol. (2001) [Pubmed]
  21. Alternative forms of Max as enhancers or suppressors of Myc-ras cotransformation. Mäkelä, T.P., Koskinen, P.J., Västrik, I., Alitalo, K. Science (1992) [Pubmed]
  22. Differential regulation of AP-1 and novel TRE-specific DNA-binding complexes during differentiation of oligodendrocyte-type-2-astrocyte (O-2A) progenitor cells. Barnett, S.C., Rosario, M., Doyle, A., Kilbey, A., Lovatt, A., Gillespie, D.A. Development (1995) [Pubmed]
  23. Id2 leaves the chromatin of the E2F4-p130-controlled c-myc promoter during hepatocyte priming for liver regeneration. Rodríguez, J.L., Sandoval, J., Serviddio, G., Sastre, J., Morante, M., Perrelli, M.G., Martínez-Chantar, M.L., Viña, J., Viña, J.R., Mato, J.M., Avila, M.A., Franco, L., López-Rodas, G., Torres, L. Biochem. J. (2006) [Pubmed]
  24. Promoter-binding and repression of PDGFRB by c-Myc are separable activities. Mao, D.Y., Barsyte-Lovejoy, D., Ho, C.S., Watson, J.D., Stojanova, A., Penn, L.Z. Nucleic Acids Res. (2004) [Pubmed]
  25. Inhibitory effect of antisense oligodeoxynucleotide to p44/p42 MAPK on angiotensin II-induced hypertrophic response in cultured neonatal rat cardiac myocyte. Zhang, S.Q., Ding, B., Guo, Z.G., Li, Y.X. Acta Pharmacol. Sin. (2004) [Pubmed]
  26. Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. Wagner, A.J., Small, M.B., Hay, N. Mol. Cell. Biol. (1993) [Pubmed]
  27. Activation of c-Myc uncouples DNA replication from activation of G1-cyclin-dependent kinases. Pusch, O., Bernaschek, G., Eilers, M., Hengstschläger, M. Oncogene (1997) [Pubmed]
  28. c-Myc induces apoptosis in epithelial cells by both p53-dependent and p53-independent mechanisms. Sakamuro, D., Eviner, V., Elliott, K.J., Showe, L., White, E., Prendergast, G.C. Oncogene (1995) [Pubmed]
  29. Implication of Bcl-2 family genes in basal and D-amphetamine-induced apoptosis in preneoplastic and neoplastic rat liver lesions. De Miglio, M.R., Muroni, M.R., Simile, M.M., Calvisi, D.F., Tolu, P., Deiana, L., Carru, A., Bonelli, G., Feo, F., Pascale, R.M. Hepatology (2000) [Pubmed]
  30. Expressions of c-myc and insulin-like growth factor-1 mRNA in the liver of growing rats vary reciprocally in response to changes in dietary protein. Kanamoto, R., Yokota, T., Hayashi, S.I. J. Nutr. (1994) [Pubmed]
  31. A modest reduction in c-myc expression has minimal effects on cell growth and apoptosis but dramatically reduces susceptibility to Ras and Raf transformation. Bazarov, A.V., Adachi, S., Li, S.F., Mateyak, M.K., Wei, S., Sedivy, J.M. Cancer Res. (2001) [Pubmed]
  32. Targeting c-Myc-activated genes with a correlation method: detection of global changes in large gene expression network dynamics. Remondini, D., O'Connell, B., Intrator, N., Sedivy, J.M., Neretti, N., Castellani, G.C., Cooper, L.N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  33. Direct activation of RNA polymerase III transcription by c-Myc. Gomez-Roman, N., Grandori, C., Eisenman, R.N., White, R.J. Nature (2003) [Pubmed]
  34. Nucleolar localization of hepatic c-Myc: a potential mechanism for c-Myc regulation. Sanders, J.A., Gruppuso, P.A. Biochim. Biophys. Acta (2005) [Pubmed]
 
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