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Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135 [J. W., K. G., K. W.], and Canji Inc., San Diego, California 92121 [K. N. W.]
During in vitro myogenesis, a portion of myoblasts undergo apoptosis, whereas others continue with their differentiation program and form myotubes that are resistant to cell death. Previous work has shown that the expression of the Cdk inhibitor p21 correlates with enhanced resistance to apoptosis and that forced expression of p21 will confer this phenotype on differentiating myocytes. Here we examine the role of the retinoblastoma gene (Rb) in myocyte survival. Compared with wild-type myocytes, CC42 (Rb-/-) myocytes undergo higher frequencies of apoptosis during mitogen deprivation-induced myogenesis. Despite these features, Rb-/- myocytes display normal up-regulation of p21 and downregulation of Cdk activities upon differentiation. Adenoviral constructs expressing the Cdk inhibitors p21 or p16 inhibit apoptosis in wild-type but not Rb-/- myocyte cultures. On the other hand, a Rb-expressing adeno-viral construct inhibited apoptosis in both cell types. These data demonstrate that Rb functions downstream from the Cdk inhibitors to coordinate cell cycle withdrawal with programmed cell death during myocyte differentiation.
1 This work was supported by NIH Grants AR40197 and HL 50692 to K. W.
2 To whom requests for reprints should be addressed, at Division of Cardiovascular Research, St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge Street, Boston, MA 02135.
Received 9/16/96. Accepted 12/17/96.
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