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PMID: 8978686 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc.

The EMBO journal ·Vol. 15 ·No. 23 ·1996-12-02 ·Pages 6595-604

Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B

Abstract

We show here that c-Myc antagonizes the cyclin-dependent kinase (CDK) inhibitor p27Kip1. p27 expressed from recombinant retroviruses in Rat1 cells associated with and inhibited cyclin E/CDK2 complexes, induced accumulation of the pRb and p130 proteins in their hypophosphorylated forms, and arrested cells in G1. Prior expression of c-Myc prevented inactivation of cyclin E/CDK2 as well as dephosphorylation of pRb and p130, and allowed continuous cell proliferation in the presence of p27. This effect did not require ubiquitin-mediated degradation of p27. Myc altered neither the susceptibility of cyclin E/CDK2 to inhibition by p27, nor the intrinsic CDK-inhibitory activity of p27, but induced sequestration of p27 in a form unable to bind cyclin E/CDK2. Neither Myc itself nor other G1-cyclin/CDK complexes were directly responsible for p27 sequestration. Retroviral expression of G1 cyclins (D1-3, E or A) or of the Cdc25A phosphatase did not overcome p27-induced arrest. Growth rescue by Myc required dimerization with Max, DNA binding and an intact transcriptional activation domain, as previously shown for cellular transformation. We propose that this activity is mediated by the product of an as yet unknown Myc-Max target gene(s) and represents an essential aspect of Myc's mitogenic and oncogenic functions.

MeSH Terms
Animals CDC2-CDC28 Kinases Cell Cycle Cell Cycle Proteins Cell Division Cell Line Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases/antagonists & inhibitors,metabolism Cyclins/metabolism Enzyme Inhibitors Genetic Vectors Humans Mice Microtubule-Associated Proteins/metabolism Protein Serine-Threonine Kinases/metabolism Proto-Oncogene Proteins c-myc/metabolism Rats Recombinant Proteins/metabolism Retroviridae Transfection Tumor Suppressor Proteins
Chemicals
Cdkn1b protein, mouse Cdkn1b protein, rat Cell Cycle Proteins Cyclins Enzyme Inhibitors Microtubule-Associated Proteins Proto-Oncogene Proteins c-myc Recombinant Proteins Tumor Suppressor Proteins Cyclin-Dependent Kinase Inhibitor p27 Protein Serine-Threonine Kinases CDC2-CDC28 Kinases CDK2 protein, human Cdk2 protein, mouse Cdk2 protein, rat Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Vlach J
Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland.
Hennecke S
Alevizopoulos K
Conti D
Amati B
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1996-12-02
Pages
6595-604
Language
English
Region
England
NLM ID
8208664
PMCID
PMC452484
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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