Cooperation between p53 and p130(Rb2) in induction of cellular senescence.
To determine pathways cooperating with p53 in cellular senescence when the retinoblastoma protein (pRb)/p16INK4a pathway is defunct, we stably transfected the p16INK4a-negative C6 rat glioma cell line with a temperature-sensitive mutant p53. Activation of p53(Val-135) induces a switch in pocket protein expression from pRb and p107 to p130(Rb2) and stalls the cells in late G1, early S-phase at high levels of cyclin E. Maintenance of the arrest depends on the functions of p130(Rb2) repressing cyclin A. Inactivation of p53 in senescent cultures restores the pocket proteins to initial levels and initiates progression into S-phase, but the cells fail to resume proliferation, likely due to DNA damage becoming apparent in the arrest and activating apoptosis subsequent to the release from p53-dependent growth suppression. The data indicate that p53 can cooperate selectively with p130(Rb2) to induce cellular senescence, a pathway that may be relevant when the pRb/p16INK4a pathway is defunct.
Kapić
A
A
Heinrich-Pette-Institute for Experimental Virology and Immunology at the University of Hamburg, Martinistr. 52, 20251 Hamburg, Germany.
Helmbold
H
H
Reimer
R
R
Klotzsche
O
O
Deppert
W
W
Bohn
W
W
D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D019925:Cyclin A / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009154:Mutation; D010641:Phenotype; D051381:Rats; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism*; D016196:S Phase; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D019925:Cyclin A; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050717:Retinoblastoma-Like Protein p130; D016159:Tumor Suppressor Protein p53; D018844:Cyclin-Dependent Kinases