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Mutant MyoD lacking Cdc2 phosphorylation sites delays M-phase entry.
Lionel A J Tintignac1, Valentina Sirri, Marie Pierre Leibovitch
1Laboratoire de Génétique Oncologique, Institut Gustave Roussy, 94805 Villejuif, France.
Molecular and Cellular Biology
|January 30, 2004
Summary
MyoD transcription factor regulates cell cycle progression by controlling p21 expression during the G(2)/M transition. MyoD phosphorylation is essential for timely entry into mitosis.
Area of Science:
- Muscle development and cell cycle regulation
- Molecular biology and cell signaling pathways
Background:
- MyoD and Myf-5 are key transcription factors for myoblast differentiation.
- These factors exhibit opposing cell cycle-specific expression patterns.
Purpose of the Study:
- To investigate the role of MyoD in the G(2)/M cell cycle transition.
- To elucidate the regulatory mechanism of p21(Waf1/Cip1) (p21) expression by MyoD.
Main Methods:
- Analysis of MyoD and p21 expression during the cell cycle in myoblasts.
- Investigating the effect of MyoD phosphorylation on its stability and transcriptional activity.
- Utilizing inducible expression of nonphosphorylable MyoD (MyoD A5/A200) and p21-deficient cells.
Main Results:
- MyoD reaccumulates in G(2) with p21; cyclin B-Cdc2 phosphorylates MyoD, decreasing its stability and down-regulating MyoD and p21.
- Nonphosphorylable MyoD (MyoD A5/A200) enhances interaction with P/CAF, boosting p21 transcription.
- Sustained p21 expression by MyoD A5/A200 inhibits cyclin B-Cdc2 kinase, causing G(2) arrest, which is absent in p21(-/-) cells.
Conclusions:
- MyoD acts as a transcriptional activator of p21 in cycling cells.
- MyoD phosphorylation is a critical regulatory step for the G(2)/M cell cycle transition.