MyoD-induced expression of p21 inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation - PubMed (original) (raw)

MyoD-induced expression of p21 inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation

K Guo et al. Mol Cell Biol. 1995 Jul.

Abstract

The terminal differentiation of C2C12 skeletal muscle cells involves the activation of unique sets of genes and an irreversible withdrawal from the cell cycle. This process is associated with a decrease in cdk2 activity in cell extracts. The decrease in cdk2 activity correlates with diminished levels of cdk2 and cyclin A and with a marked induction of the p21 cyclin-dependent kinase (cdk) inhibitor. The upregulation of p21 occurred at the levels of mRNA and protein, and p21 formed a complex with the cyclin kinases in myotubes. Further, the immunodepletion of p21 from myotube extracts neutralized the heat-stable cdk2 inhibitory activity that was induced upon myogenic differentiation. The levels of p21 mRNA, protein, and activity remained constant in myotubes when they were reexposed to mitogen-rich growth medium, indicating that permanent changes in the cell's genetic program contribute to its sustained expression following terminal differentiation. Indeed, 10T1/2 fibroblasts transformed with the myogenic factor MyoD, but not the parental multipotent cells, upregulated p21 transcript levels when induced to differentiate by serum withdrawal, demonstrating that the upregulation is an integral feature of myogenic commitment and differentiation. The functional consequences of this upregulation were indicated by ectopically expressing p21 in myoblasts; this was sufficient for cell cycle arrest in mitogen-rich growth medium. The induction and sustained expression of p21 appears to be a contributory mechanism by which myocytes irreversibly exit the cell cycle upon terminal differentiation.

PubMed Disclaimer

Similar articles

• Uncoupling of p21 induction and MyoD activation results in the failure of irreversible cell cycle arrest in doxorubicin-treated myocytes.
  Puri PL, Medaglia S, Cimino L, Maselli C, Germani A, De Marzio E, Levrero M, Balsano C. Puri PL, et al. J Cell Biochem. 1997 Jul 1;66(1):27-36. doi: 10.1002/(sici)1097-4644(19970701)66:1<27::aid-jcb4>3.0.co;2-#. J Cell Biochem. 1997. PMID: 9215525
• Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD.
  Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D, Lassar AB. Halevy O, et al. Science. 1995 Feb 17;267(5200):1018-21. doi: 10.1126/science.7863327. Science. 1995. PMID: 7863327
• Regulation of MyoD function in the dividing myoblast.
  Wei Q, Paterson BM. Wei Q, et al. FEBS Lett. 2001 Feb 16;490(3):171-8. doi: 10.1016/s0014-5793(01)02120-2. FEBS Lett. 2001. PMID: 11223032 Review.
• Crosstalk between cell cycle regulators and the myogenic factor MyoD in skeletal myoblasts.
  Kitzmann M, Fernandez A. Kitzmann M, et al. Cell Mol Life Sci. 2001 Apr;58(4):571-9. doi: 10.1007/PL00000882. Cell Mol Life Sci. 2001. PMID: 11361092 Free PMC article. Review.

Cited by

• Inhibition of Notch3 signalling induces rhabdomyosarcoma cell differentiation promoting p38 phosphorylation and p21(Cip1) expression and hampers tumour cell growth in vitro and in vivo.
  Raimondi L, Ciarapica R, De Salvo M, Verginelli F, Gueguen M, Martini C, De Sio L, Cortese G, Locatelli M, Dang TP, Carlesso N, Miele L, Stifani S, Limon I, Locatelli F, Rota R. Raimondi L, et al. Cell Death Differ. 2012 May;19(5):871-81. doi: 10.1038/cdd.2011.171. Epub 2011 Nov 25. Cell Death Differ. 2012. PMID: 22117196 Free PMC article.
• An atlas of caspase cleavage events in differentiating muscle cells.
  Gomez-Cardona E, Dehkordi MH, Van Baar K, Vitkauskaite A, Julien O, Fearnhead HO. Gomez-Cardona E, et al. Protein Sci. 2024 Sep;33(9):e5156. doi: 10.1002/pro.5156. Protein Sci. 2024. PMID: 39180494 Free PMC article.
• Proteomic Assessment of the Relevant Factors Affecting Pork Meat Quality Associated with Longissimus dorsi Muscles in Duroc Pigs.
  Cho JH, Lee RH, Jeon YJ, Park SM, Shin JC, Kim SH, Jeong JY, Kang HS, Choi NJ, Seo KS, Cho YS, Kim MS, Ko S, Seo JM, Lee SY, Shim JH, Chae JI. Cho JH, et al. Asian-Australas J Anim Sci. 2016 Nov;29(11):1653-1663. doi: 10.5713/ajas.16.0050. Epub 2016 Mar 30. Asian-Australas J Anim Sci. 2016. PMID: 27165031 Free PMC article.
• Coordinated regulation of Rap1 and thyroid differentiation by cyclic AMP and protein kinase A.
  Tsygankova OM, Saavedra A, Rebhun JF, Quilliam LA, Meinkoth JL. Tsygankova OM, et al. Mol Cell Biol. 2001 Mar;21(6):1921-9. doi: 10.1128/MCB.21.6.1921-1929.2001. Mol Cell Biol. 2001. PMID: 11238928 Free PMC article.
• Global regulation of alternative splicing during myogenic differentiation.
  Bland CS, Wang ET, Vu A, David MP, Castle JC, Johnson JM, Burge CB, Cooper TA. Bland CS, et al. Nucleic Acids Res. 2010 Nov;38(21):7651-64. doi: 10.1093/nar/gkq614. Epub 2010 Jul 15. Nucleic Acids Res. 2010. PMID: 20634200 Free PMC article.

References

1. 1. Genes Dev. 1994 Dec 15;8(24):2939-52 - PubMed
2. 1. Cell. 1994 Nov 18;79(4):551-5 - PubMed
3. 1. Cell. 1978 Nov;15(3):855-64 - PubMed
4. 1. Biochem Biophys Res Commun. 1995 Jan 5;206(1):82-8 - PubMed
5. 1. Science. 1995 Feb 17;267(5200):1018-21 - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Atypon
  • Europe PubMed Central
  • PubMed Central

• Other Literature Sources

  • The Lens - Patent Citations Database