p53-mediated accumulation of hypophosphorylated pRb after the G1 restriction point fails to halt cell cycle progression.
This study analyses whether the inability of p53 to induce G1 arrest after the restriction point relates to an inability to modulate pRb phosphorylation. Transient p53 overexpression in normal human diploid fibroblasts and p53-deficient cancer cells led to increased levels of the cyclin-dependent kinase inhibitor p21 cip1/Waf1/Sdi1 and an accumulation of hypophosphorylated pRb in cells growing asynchronously and in cells synchronized in late G1 or M. Similarly, gamma-irradiation of asynchronous, late-G1, or S phase fibroblasts led to an increase in hypophosphorylated pRb. Experiments with fibroblasts expressing the HPV16 E6 protein indicated that accumulation of hypophosphorylated pRb required functional p53. Progression into and through S phase was not altered by the presence of hypophosphorylated pRb in late G1, consistent with the failure of p53 to mediate G1 arrest in cells that are past the restriction point. These data indicate that accumulation of hypophosphorylated pRb has significantly different effects on cell cycle progression in early G1 versus late G1 or S phase.
Linke
S P
SP
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Harris
M P
MP
Neugebauer
S E
SE
Clarkin
K C
KC
Shepard
H M
HM
Maneval
D C
DC
Wahl
G M
GM
D002289:Carcinoma, Non-Small-Cell Lung; D002453:Cell Cycle / Q000502:physiology* / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000096:biosynthesis* / Q000378:metabolism; D004171:Diploidy; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts; D016193:G1 Phase; D005720:Gamma Rays; D006801:Humans; D008175:Lung Neoplasms; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis; D027383:Papillomaviridae / Q000235:genetics; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000378:metabolism*; D016196:S Phase; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C068651:E6 protein, Human papillomavirus type 16; D004791:Enzyme Inhibitors; D009856:Oncogene Proteins, Viral; D011994:Recombinant Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D018844:Cyclin-Dependent Kinases