Accumulation of p16INK4a in mouse fibroblasts as a function of replicative senescence and not of retinoblastoma gene status.
Viral transformation of mouse and human fibroblasts has very different effects on the composition of cyclin-dependent kinase (Cdk) complexes. In human cells transformed by the large T-antigen of simian virus 40 (SV40 T-Ag) and human tumour cell lines that lack a functional retinoblastoma gene product (pRb) no cyclin D1-Cdk4 complexes can be detected because all the available Cdk4 is associated with the Cdk-inhibitor p16INK4a. In contrast, SV40-transformed mouse cells and fibroblasts from Rh1-nullizygous mouse embryos contain normal levels of cyclin D1-Cdk4 complexes. To investigate this species difference, we have compared the biochemical properties and expression of mouse p16INK4a with that of its human counterpart. There is a marked increase in p16 RNA and protein levels as primary embryo fibroblasts approach their finite lifespan in culture, but mouse p16 expression does not appear to be influenced by the status of pRb. Transformed or spontaneously immortalized mouse cells therefore do not achieve the very high levels of p16 characteristic of pRb-negative human cell lines. We suggest that these differences may be related to the different frequencies with which mouse and human cells can be immortalized in culture.
Palmero
I
I
Molecular Oncology Laboratory, Imperial Cancer Research Fund, London, UK.
McConnell
B
B
Parry
D
D
Brookes
S
S
Hara
E
E
Bates
S
S
Jat
P
P
Peters
G
G
D016475:3T3 Cells / Q000821:virology; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002461:Cell Line, Transformed / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D014158:Transcription, Genetic
D000952:Antigens, Polyomavirus Transforming; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016213:Cyclins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D019938:Cyclin D1; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases