Sequential extension of proliferative lifespan in human fibroblasts induced by over-expression of CDK4 or 6 and loss of p53 function
Language: 
English
Abstract: 

Replicative senescence is thought to be a significant barrier to human tumorigenesis, which in human fibroblasts, and many other cell types, can be overcome experimentally by combined loss of function of p53 and Rb 'pathways'. To avoid the confounding pleiotropic effects of HPVE7 frequently used in such studies, here we have employed retroviral vectors over-expressing CDK4 or CDK6 as a more representative model of naturally-occurring mutations targeting the Rb pathway. We show that these can extend fibroblast lifespan by approximately 10 population doublings, ending in a viable senescence-like state which contrasts with the apoptotic end-stage seen with E7. Compared with 'normal' senescence, this growth arrest was, in most cases, not accompanied by any further increase in p21(Waf1) levels but with up to a 19-fold increase in p16(Ink4a). Surprisingly however, this could not explain arrest, since expression of mutant CDK4 and/or CDK6, incapable of binding p16(Ink4a), did not confer any greater lifespan extension than the wild-type CDKs. Subsequent abrogation of p53 function by a second vector, encoding HPVE6, downregulated p21(Waf1) and conferred a second lifespan extension, ending in a crisis-like state, consistent with full escape from senescence. These data: (i) point to a back-up 'senescence' mechanism distinct from induction of p21(Waf1) or p16(Ink4a); and (ii) provide an in vitro model of clonal evolution through successive dysfunction of Rb and p53 pathways in a relevant human cell context.

Author(s): 
Morris, Mark
Hepburn, Peter
Wynford-Thomas, David
Item Type: 
Journal Article
Publication Title: 
Oncogene
Journal Abbreviation: 
Oncogene
Publication Date: 
6/20/2002
Publication Year: 
2002
Pages: 
4277-4288
Volume: 
21
Issue: 
27
ISSN: 
0950-9232
DOI: 
10.1038/sj.onc.1205492
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 12082615

Turabian/Chicago Citation

Mark Morris, Peter Hepburn and David Wynford-Thomas. 6/20/2002. "Sequential extension of proliferative lifespan in human fibroblasts induced by over-expression of CDK4 or 6 and loss of p53 function." Oncogene 21: 27: 4277-4288. 10.1038/sj.onc.1205492.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1038/sj.onc.1205492 | issn = 0950-9232 | volume = 21 | pages = 4277-4288 | last = Morris | first = Mark | coauthors = Hepburn, Peter, Wynford-Thomas, David | title = Sequential extension of proliferative lifespan in human fibroblasts induced by over-expression of CDK4 or 6 and loss of p53 function | journal = Oncogene | date = 6/20/2002 | pmid = | pmc = }} </ref>