Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts.
Heterokaryon studies suggest that senescent and quiescent human diploid fibroblasts (HDF) contain a common inhibitor of entry into S phase. DNA synthesis can be induced in senescent and quiescent HDF by fusing them with cells containing DNA viral oncogenes such as SV40 T antigen, adenovirus E1A, or human papillomavirus E7. Both senescent and quiescent HDF contained the unphosphorylated form (p110Rb) of the retinoblastoma protein, a putative inhibitor of proliferation. After serum stimulation, senescent HDF did not phosphorylate p110Rb and did not enter S phase, whereas quiescent HDF phosphorylated p110Rb and entered S phase. These findings, combined with the observations that T antigen, E1A, and E7 form complexes with, and presumably inactivate, unphosphorylated p110Rb, suggest that failure to phosphorylate p110Rb may be an immediate cause of failure to enter S phase in senescent HDF.
Stein
G H
GH
Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder 80309-0347.
Beeson
M
M
Gordon
L
L
D017456:Adenovirus Early Proteins; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002455:Cell Division; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007399:Interphase; D008970:Molecular Weight; D009687:Nuclear Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D009857:Oncogenes; D027383:Papillomaviridae / Q000235:genetics; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism*; D010766:Phosphorylation; D016160:Retinoblastoma Protein; D013539:Simian virus 40 / Q000235:genetics / Q000276:immunology
D017456:Adenovirus Early Proteins; D000952:Antigens, Polyomavirus Transforming; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D010750:Phosphoproteins; D016160:Retinoblastoma Protein