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p53-independent expression of p21Cip1 in muscle and other terminally differentiating cells
S B Parker1, G Eichele, P Zhang
1Department of Biochemistry, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030.
Abstract:
Terminal differentiation is coupled to withdrawal from the cell cycle. The cyclin-dependent kinase inhibitor (CKI) p21Cip1 is transcriptionally regulated by p53 and can induce growth arrest. CKIs are therefore potential mediators of developmental control of cell proliferation. The expression pattern of mouse p21 correlated with terminal differentiation of multiple cell lineages including skeletal muscle, cartilage, skin, and nasal epithelium in a p53-independent manner. Although the muscle-specific transcription factor MyoD is sufficient to activate p21 expression in 10T1/2 cells, p21 was expressed in myogenic cells of mice lacking the genes encoding MyoD and myogenin, demonstrating that p21 expression does not require these transcription factors. The p21 protein may function during development as an inducible growth inhibitor that contributes to cell cycle exit and differentiation.
Insights
The cyclin-dependent kinase inhibitor p21Cip1 promotes cell cycle exit and differentiation during development. Its expression in various cell types occurs independently of p53 and key muscle transcription factors.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Biology
Background:
- Terminal differentiation, a process where cells become specialized, is linked to cell cycle arrest.
- Cyclin-dependent kinase inhibitors (CKIs) like p21Cip1 regulate cell proliferation and are implicated in developmental control.
- p21Cip1 is known to be transcriptionally regulated by p53 and can induce growth arrest.
Purpose of the Study:
- To investigate the role and regulation of p21Cip1 during terminal differentiation in vivo.
- To determine if p21Cip1 expression during differentiation is dependent on p53 or specific muscle transcription factors.
Main Methods:
- Analysis of p21 expression patterns in various differentiating cell lineages in mice.
- Examination of p21 expression in mice lacking genes for transcription factors like MyoD and myogenin.
- Assessment of p21 expression in relation to p53 status.
Main Results:
- Mouse p21 expression correlated with terminal differentiation across multiple cell types, including muscle, cartilage, skin, and nasal epithelium.
- p21 expression during differentiation occurred independently of p53.
- p21 was expressed in myogenic cells even in the absence of MyoD and myogenin, indicating these factors are not required for its differentiation-linked expression.
Conclusions:
- p21Cip1 functions as an inducible growth inhibitor during development, contributing to cell cycle exit and differentiation.
- The expression of p21 during terminal differentiation is regulated in a p53-independent and MyoD/myogenin-independent manner in vivo.