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FoxO3a preferentially induces p27 Kip1 expression while impairing muscle precursor cell‐cycle progression
Author(s) -
Rathbone Christopher R.,
Booth Frank W.,
Lees Simon J.
Publication year - 2008
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.20897
Subject(s) - retinoblastoma protein , cell growth , biology , skeletal muscle , cell cycle , transcription factor , cyclin e , cyclin d1 , muscle atrophy , cyclin dependent kinase 2 , microbiology and biotechnology , cancer research , kinase , cyclin , endocrinology , protein kinase a , cell , biochemistry , gene
Previous work has demonstrated that forkhead transcription factors, which include the FoxO subfamily, play a critical role in muscle atrophy by inducing expression of the atrophy‐related ubiquitin ligases. The proliferation of muscle precursor cells (MPC) is also essential for skeletal muscle mass. The hypothesis was tested that the FoxO forkhead transcription factor FoxO3a hinders MPC proliferation. The present studies were designed to determine the effects of overexpression of FoxO3a on in vitro proliferation of MPCs. MPCs infected with an adenovirus for wild‐type FoxO3a had decreased DNA synthesis as detected by the incorporation of 5‐bromo‐2′ deoxyuridine. In general, cyclin‐dependent kinase inhibitors, including p27 Kip1 and p21 Waf/Cip1 , inhibit cell proliferation. Associated with the impaired MPC proliferation, we found an increase in the promoter activity and protein levels of the cyclin‐dependent kinase inhibitor p27 Kip1 , whereas there was no effect and a decrease in the promoter activity and protein levels of p21 Waf/Cip1 . FoxO3a overexpression had no effect on either the phosphorylation of retinoblastoma protein (ser780) or cyclin D1 protein levels, suggesting that FoxO3a does not effect the early phase of the G 1 –S transition. In addition to its ability to induce muscle atrophy, these studies identify FoxO3a as a negative regulator of MPC proliferation. Our findings suggest that attenuating increased FoxO3a may restore MPC proliferation to prevent atrophy and improve the regenerative capacity of skeletal muscle. Muscle Nerve, 2007