Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins.

Details

Serval ID
serval:BIB_816
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cyclin E and c-Myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins.
Journal
EMBO Journal
Author(s)
Alevizopoulos K., Vlach J., Hennecke S., Amati B.
ISSN
0261-4189
Publication state
Published
Issued date
1997
Volume
16
Number
17
Pages
5322-5333
Language
english
Notes
Publication types: Journal Article
Abstract
Retroviral expression of the cyclin-dependent kinase (CDK) inhibitor p16(INK4a) in rodent fibroblasts induces dephosphorylation of pRb, p107 and p130 and leads to G1 arrest. Prior expression of cyclin E allows S-phase entry and long-term proliferation in the presence of p16. Cyclin E prevents neither the dephosphorylation of pRb family proteins, nor their association with E2F proteins in response to p16. Thus, cyclin E can bypass the p16/pRb growth-inhibitory pathway downstream of pRb activation. Retroviruses expressing E2F-1, -2 or -3 also prevent p16-induced growth arrest but are ineffective against the cyclin E-CDK2 inhibitor p27(Kip1), suggesting that E2F cannot substitute for cyclin E activity. Thus, cyclin E possesses an E2F-independent function required to enter S-phase. However, cyclin E may not simply bypass E2F function in the presence of p16, since it restores expression of E2F-regulated genes such as cyclin A or CDC2. Finally, c-Myc bypasses the p16/pRb pathway with effects indistinguishable from those of cyclin E. We suggest that this effect of Myc is mediated by its action upstream of cyclin E-CDK2, and occurs via the neutralization of p27(Kip1) family proteins, rather than induction of Cdc25A. Our data imply that oncogenic activation of c-Myc, and possibly also of cyclin E, mimics loss of the p16/pRb pathway during oncogenesis.
Keywords
3T3 Cells, Animals, Carrier Proteins, Cell Cycle Proteins, Cell Division/physiology, Cyclin E/metabolism, Cyclin-Dependent Kinase Inhibitor p16/metabolism, DNA-Binding Proteins, E2F Transcription Factors, E2F1 Transcription Factor, Mice, Nuclear Proteins/metabolism, Phosphoproteins/genetics, Phosphoproteins/metabolism, Phosphorylation, Proteins, Proto-Oncogene Proteins c-myc/metabolism, Rats, Recombinant Proteins/metabolism, Retinoblastoma Protein/genetics, Retinoblastoma Protein/metabolism, Retinoblastoma-Like Protein p107, Retinoblastoma-Like Protein p130, Retroviridae/genetics, Transcription Factor DP1, Transcription Factors/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
19/11/2007 12:46
Last modification date
20/08/2019 14:41
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