Uncoupling of p21 induction and MyoD activation results in the failure of irreversible cell cycle arrest in doxorubicin-treated myocytes

Pier Lorenzo Puri, Stefania Medaglia, Letizia Cimino, Carlo Maselli, Antonia Germani, Elisabetta De Marzio, Massimo Levrero, Clara Balsano

Research output: Contribution to journalArticle

Abstract

Doxorubicin (Dox, Adriamicin), a potent broad spectrum anthracycline anticancer drug, selectively inhibits muscle specific gene expression in cardiac cells in vivo and prevents terminal differentiation of skeletal muscle cells in vitro. By inducing the expression of the helix-loop-helix (HLH) transcriptional inhibitor Id2, Dox represses the myogenic function of the MyoD family of muscle regulatory factors (MRFs). In many cell types, terminal differentiation is coupled to an irreversible exit from the cell cycle and MyoD plays a critical role in the permanent cell cycle arrest of differentiating myocytes by upregulating the cyclin dependent kinase inhibitor (cdki) p21. Here, we correlate Dox effects on cell cycle with changes of E2F/DP complexes and activity in differentiating C2C12 myocytes. In Dox-treated quiescent myoblasts, which fail to differentiate into myotubes under permissive culture conditions, serum re-stimulation induces cyclin/cdk re association on the E2F/DP complexes and this correlates with an evident increase in E2F/DP driven transcription and re-entry of myoblasts into the cell cycle. Despite Dox ability to activate the DNA-damage dependent p53/p21 pathway, when induced in the absence of MyoD or other MRFs, p21 fails to maintain the postmitotic state in Dox-treated myocytes induced to differentiate. Thus, uncoupling p21 induction and MyoD activity results in a serum-reversible cell cycle arrest, indicating that MRF specific activation of cdki(s) is required for permanent cell cycle arrest in differentiating muscle cells.

Original languageEnglish
Pages (from-to)27-36
Number of pages10
JournalJournal of Cellular Biochemistry
Volume66
Issue number1
DOIs
Publication statusPublished - Jul 1 1997

Keywords

  • Cell cycle
  • Doxorubicin/adriamicin
  • E2F
  • MyoD
  • p21

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Uncoupling of p21 induction and MyoD activation results in the failure of irreversible cell cycle arrest in doxorubicin-treated myocytes'. Together they form a unique fingerprint.

  • Cite this