MyoD induces apoptosis in the absence of RB function through a p21(WAF1)-dependent re-localization of cyclin/cdk complexes to the nucleus.
During differentiation of skeletal myoblasts, MyoD promotes growth arrest through the induction of the cdk inhibitor p21 and the accumulation of hypophosphorylated RB protein. Myoblasts lacking RB function fail to accomplish full differentiation and undergo apoptosis. Here we show that exogenous MyoD induces apoptosis in several cell backgrounds sharing RB inactivation. This process is associated with increased levels of cell cycle-driving proteins and aberrant cell cycle progression. The inability of MyoD to induce apoptosis in a p21-null background, highlights a requirement of p21 in RB-regulated apoptosis during myogenesis. This pro-apoptotic function of p21 cannot be exerted by simple p21 over-expression, but requires the co-operation of MyoD. We also suggest that the essential aspect of p21 activity involved in such a process is related to its ability to induce the nuclear accumulation and aberrant activity of cyclin/cdk complexes. These results establish a novel link between MyoD, p21 and RB during myogenesis, providing new insights into the antagonism between muscle differentiation and loss of RB function.
Peschiaroli
Angelo
A
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Biotecnologie Cellulari ed Ematologia, Sezione di Genetica Molecolare, Università di Roma La Sapienza, Viale Regina Elena 324, 00161 Roma, Italy.
Figliola
Rocco
R
Coltella
Luana
L
Strom
Alessandra
A
Valentini
Alessandra
A
D'Agnano
Igea
I
Maione
Rossella
R
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D016161:Genes, Retinoblastoma; D011905:Genes, ras; D006801:Humans; D046911:Macromolecular Substances; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology*; D017570:MyoD Protein / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000502:physiology*; D014162:Transfection
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D046911:Macromolecular Substances; D017570:MyoD Protein; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases