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PMID: 10713180 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Cooperation of p27(Kip1) and p18(INK4c) in progestin-mediated cell cycle arrest in T-47D breast cancer cells.

Molecular and cellular biology ·Vol. 20 ·No. 7 ·2000-04-00 ·Pages 2581-91

Swarbrick A, Lee CS, Sutherland RL, Musgrove EA

Abstract

The steroid hormone progesterone regulates proliferation and differentiation in the mammary gland and uterus by cell cycle phase-specific actions. The long-term effect of progestins on T-47D breast cancer cells is inhibition of cellular proliferation. This is accompanied by decreased G(1) cyclin-dependent kinase (CDK) activities, redistribution of the CDK inhibitor p27(Kip1) among these CDK complexes, and alterations in the elution profile of cyclin E-Cdk2 upon gel filtration chromatography, such that high-molecular-weight complexes predominate. This study aimed to determine the relative contribution of CDK inhibitors to these events. Following progestin treatment, the majority of cyclin E- and D-CDK complexes were bound to p27(Kip1) and few were bound to p21(Cip1). In vitro, recombinant His(6)-p27 could quantitatively reproduce the effects on cyclin E-Cdk2 kinase activity and the shift in molecular weight observed following progestin treatment. In contrast, cyclin D-Cdk4 was not inhibited by His(6)-p27 in vitro or p27(Kip1) in vivo. However, an increase in the expression of the Cdk4/6 inhibitor p18(INK4c) and its extensive association with Cdk4 and Cdk6 were apparent following progestin treatment. Recombinant p18(INK4c) led to the reassortment of cyclin-CDK-CDK inhibitor complexes in vitro, with consequent decrease in cyclin E-Cdk2 activity. These results suggest a concerted model of progestin action whereby p27(Kip1) and p18(INK4c) cooperate to inhibit cyclin E-Cdk2 and Cdk4. Since similar models have been developed for growth inhibition by transforming growth factor beta and during adipogenesis, interaction between the Cip/Kip and INK4 families of inhibitors may be a common theme in physiological growth arrest and differentiation.

MeSH Terms
Breast Neoplasms/metabolism Carrier Proteins/metabolism Cell Cycle/drug effects Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p18 Cyclin-Dependent Kinase Inhibitor p27 Cyclin-Dependent Kinases/metabolism Cyclins/metabolism Enzyme Inhibitors/pharmacology Gene Expression Regulation, Neoplastic/drug effects Microtubule-Associated Proteins/metabolism Pregnenediones/pharmacology Progestins/pharmacology RNA, Messenger/metabolism Recombinant Proteins/metabolism Tumor Cells, Cultured Tumor Suppressor Proteins
Chemicals
Carrier Proteins Cell Cycle Proteins Cyclin-Dependent Kinase Inhibitor p18 Cyclins Enzyme Inhibitors Microtubule-Associated Proteins Pregnenediones Progestins RNA, Messenger Recombinant Proteins Tumor Suppressor Proteins Cyclin-Dependent Kinase Inhibitor p27 16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione Cyclin-Dependent Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Swarbrick A
Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia.
Lee C S
Sutherland R L
Musgrove E A
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.7.2581-2591.2000
Published
2000-04-00
Pages
2581-91
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85474
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.20.7.2581-2591.2000 PMC Full Text View journal details
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