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PMID: 19564413 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Estrogen regulation of cyclin E2 requires cyclin D1 but not c-Myc.

Molecular and cellular biology ·Vol. 29 ·No. 17 ·2009-09-00 ·Pages 4623-39

Caldon CE, Sergio CM, Schütte J, Boersma MN, Sutherland RL, Carroll JS, Musgrove EA

Abstract

During estrogen-induced proliferation, c-Myc and cyclin D1 initiate independent pathways that activate cyclin E1-Cdk2 by sequestration and/or downregulation of the CDK inhibitor p21(Waf1/Cip1), without significant increases in cyclin E1 protein levels. In contrast, cyclin E2 undergoes a marked increase in expression, which occurs within 9 to 12 h of estrogen treatment of antiestrogen-pretreated MCF-7 breast cancer cells. Both E cyclins are important to estrogen action, as small interfering RNA (siRNA)-mediated knockdown of either cyclin E1 or cyclin E2 attenuated estrogen-mediated proliferation. Inducible expression of cyclin D1 upregulated cyclin E2, while siRNA-mediated knockdown of cyclin D1 attenuated estrogen effects on cyclin E2. However, manipulation of c-Myc levels did not profoundly affect cyclin E2. Cyclin E2 induction by estrogen was accompanied by recruitment of E2F1 to the cyclin E1 and E2 promoters, and cyclin D1 induction was sufficient for E2F1 recruitment. siRNA-mediated knockdown of the chromatin remodelling factor CHD8 prevented cyclin E2 upregulation. Together, these data indicate that cyclin E2-Cdk2 activation by estrogen occurs via E2F- and CHD8-mediated transcription of cyclin E2 downstream of cyclin D1. This contrasts with the predominant regulation of cyclin E1-Cdk2 activity via CDK inhibitor association downstream of both c-Myc and cyclin D1 and indicates that cyclins E1 and E2 are not always coordinately regulated.

MeSH Terms
Animals Breast Neoplasms Cell Line, Tumor/drug effects,metabolism Cyclin D1/genetics,metabolism Cyclin E/genetics,metabolism Cyclin-Dependent Kinase 2/genetics,metabolism Cyclins/genetics,metabolism DNA-Binding Proteins/genetics,metabolism E2F Transcription Factors/genetics,metabolism Enzyme Activation Estrogens/metabolism,pharmacology Female Gene Expression Regulation, Neoplastic/drug effects Humans Mice Oncogene Proteins/genetics,metabolism Promoter Regions, Genetic Proto-Oncogene Proteins c-myc/genetics,metabolism RNA, Small Interfering/genetics,metabolism Transcription Factors/genetics,metabolism
Chemicals
CCNE1 protein, human CCNE2 protein, human CHD8 protein, human Cyclin E Cyclins DNA-Binding Proteins E2F Transcription Factors Estrogens Oncogene Proteins Proto-Oncogene Proteins c-myc RNA, Small Interfering Transcription Factors Cyclin D1 CDK2 protein, human Cyclin-Dependent Kinase 2
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Caldon C Elizabeth
Cancer Research Program, Garvan Institute of Medical Research, NSW, Australia.
Sergio C Marcelo
Schütte Judith
Boersma Marijke N
Sutherland Robert L
Carroll Jason S
Musgrove Elizabeth A
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.00269-09
Published
2009-09-00
Epub
2009-00-29
Pages
4623-39
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2725719
Subset
IM
Grants
Cancer Research UK · United Kingdom
External Links
PubMed source DOI: 10.1128/MCB.00269-09 PMC Full Text View journal details
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