Regulation of MyoD function in the dividing myoblast

Proliferating myoblasts express MyoD, yet no phenotypic markers are activat ed as long as mitogen levels are sufficient to keep the cells dividing. Dep ending upon mitogen levels, a decision is made in ct that commits the myobl ast to either continue to divide or to exit from the cell cycle and activat e terminal differentiation. Ectopic expression of MyoD under the control of the RSV or CMV promoters causes 10T1/2 cells to rapidly exit the cell cycl e and differentiate as single myocytes, even in growth medium, whereas expr ession of MgoD under the weaker SV40 promoter is compatible with proliferat ion. Coexpression of MyoD and cyclin D1, but not cyclins A, B, E or D3, blo cks transactivation of a MyoD responsive reporter. Similarly, transfection of myoblasts with the cyclin-dependent kinase (cdk) inhibitors p16 and p21 supports some muscle-specific gene expression even in growth medium. Taken altogether, these results suggest cell cycle progression negatively regulat es myocyte differentiation, possibly through a mechanism involving the D1 r esponsive cdks. We review evidence coupling growth status, the cell cycle a nd myogenesis. We describe a novel mitogen-sensitive mechanism that involve s the cyclin D1-dependent direct interaction between the G1 cdks and MyoD i n the dividing myoblast, which regulates MyoD function in a mitogen-sensiti ve manner. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.