Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation.
The experiments reported here document that the tumor suppressor retinoblastoma protein (pRB) plays an important role in the production and maintenance of the terminally differentiated phenotype of muscle cells. We show that pRB inactivation, through either phosphorylation, binding to T antigen, or genetic alteration, inhibits myogenesis. Moreover, inactivation of pRB in terminally differentiated cells allows them to reenter the cell cycle. In addition to its involvement in the myogenic activities of MyoD, pRB is also required for the cell growth-inhibitory activity of this myogenic factor. We also show that pRB and MyoD directly bind to each other, both in vivo and in vitro, through a region that involves the pocket and the basic-helix-loop-helix domains, respectively. All the results obtained are consistent with the proposal that the effects of MyoD on the cell cycle and of pRB on the myogenic pathway result from the direct binding of the two molecules.
Howard Hughes Medical Institute, Children's Hospital, Boston, Massachusetts 02115.
W
W
Gu
J W
JW
Schneider
G
G
Condorelli
S
S
Kaushal
V
V
Mahdavi
B
B
Nadal-Ginard
D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D002454:Cell Differentiation; D004261:DNA Replication; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000502:physiology*; D009132:Muscles / Q000166:cytology*; D017570:MyoD Protein; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000502:physiology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000952:Antigens, Polyomavirus Transforming; D009124:Muscle Proteins; D017570:MyoD Protein; D009838:Oligodeoxyribonucleotides; D016160:Retinoblastoma Protein; D016203:CDC2 Protein Kinase