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PMID: 9311992 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 16 ·No. 17 ·1997-09-01 ·Pages 5322-33

Alevizopoulos K, Vlach J, Hennecke S, Amati B

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.

MeSH Terms
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,metabolism Phosphorylation Proteins Proto-Oncogene Proteins c-myc/metabolism Rats Recombinant Proteins/metabolism Retinoblastoma Protein/genetics,metabolism Retinoblastoma-Binding Protein 1 Retinoblastoma-Like Protein p107 Retinoblastoma-Like Protein p130 Retroviridae/genetics Transcription Factor DP1 Transcription Factors/metabolism
Chemicals
Arid4a protein, mouse Carrier Proteins Cell Cycle Proteins Cyclin E Cyclin-Dependent Kinase Inhibitor p16 DNA-Binding Proteins E2F Transcription Factors E2F1 Transcription Factor E2f1 protein, mouse E2f1 protein, rat Nuclear Proteins Phosphoproteins Proteins Proto-Oncogene Proteins c-myc Rbl1 protein, mouse Rbl2 protein, mouse Rbl2 protein, rat Recombinant Proteins Retinoblastoma Protein Retinoblastoma-Binding Protein 1 Retinoblastoma-Like Protein p107 Retinoblastoma-Like Protein p130 Transcription Factor DP1 Transcription Factors
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Alevizopoulos K
Swiss Institute for Experimental Cancer Research, CH-1066 Epalinges, Switzerland.
Vlach J
Hennecke S
Amati B
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/16.17.5322
Published
1997-09-01
Pages
5322-33
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1170164
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/16.17.5322 PMC Full Text View journal details
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