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PMID: 16705174 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cyclin D1 regulates cellular migration through the inhibition of thrombospondin 1 and ROCK signaling.

Molecular and cellular biology ·Vol. 26 ·No. 11 ·2006-06-00 ·Pages 4240-56

Li Z, Wang C, Jiao X, Lu Y, Fu M, Quong AA, Dye C, Yang J, Dai M, Ju X, Zhang X, Li A, Burbelo P, Stanley ER, Pestell RG

Abstract

Cyclin D1 is overexpressed in human tumors, correlating with cellular metastasis, and is induced by activating Rho GTPases. Herein, cyclin D1-deficient mouse embryo fibroblasts (MEFs) exhibited increased adhesion and decreased motility compared with wild-type MEFs. Retroviral transduction of cyclin D1 reversed these phenotypes. Mutational analysis of cyclin D1 demonstrated that its effects on cellular adhesion and migration were independent of the pRb and p160 coactivator binding domains. Genomewide expression arrays identified a subset of genes regulated by cyclin D1, including Rho-activated kinase II (ROCKII) and thrombospondin 1 (TSP-1). cyclin D1(-/-) cells showed increased Rho GTP and ROCKII activity and signaling, with increased phosphorylation of LIM kinase, cofilin (Ser3), and myosin light chain 2 (Thr18/Ser19). Cyclin D1 repressed ROCKII and TSP-1 expression, and the migratory defect of cyclin D1(-/-) cells was reversed by ROCK inhibition or TSP-1 immunoneutralizing antibodies. cyclin E knockin to the cyclin D1(-/-) MEFs rescued the DNA synthesis defect of cyclin D1(-/-) MEFs but did not rescue either the migration defect or the abundance of ROCKII. Cyclin D1 promotes cellular motility through inhibiting ROCK signaling and repressing the metastasis suppressor TSP-1.

MeSH Terms
Animals Cell Adhesion Cell Movement Cells, Cultured Cyclin D1/chemistry,deficiency,metabolism Cyclin-Dependent Kinase Inhibitor p16/metabolism Cyclin-Dependent Kinases/metabolism DNA/biosynthesis Fibroblasts/cytology Gene Expression Regulation Humans Intracellular Signaling Peptides and Proteins Mice Mutation/genetics Protein Serine-Threonine Kinases/metabolism Protein Structure, Tertiary RNA, Messenger/genetics,metabolism Signal Transduction Stress Fibers/metabolism Thrombospondin 1/antagonists & inhibitors,genetics,metabolism rho-Associated Kinases
Chemicals
Cyclin-Dependent Kinase Inhibitor p16 Intracellular Signaling Peptides and Proteins RNA, Messenger Thrombospondin 1 Cyclin D1 DNA Protein Serine-Threonine Kinases rho-Associated Kinases Cyclin-Dependent Kinases
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Li Zhiping
Thomas Jefferson University, Department of Cancer Biology, Kimmel Cancer Center, Bluemle Building, Rm 1050, 233 South 10th St, Philadelphia, PA 19107, USA.
Wang Chenguang
Jiao Xuanmao
Lu Yinan
Fu Maofu
Quong Andrew A
Dye Chip
Yang Jianguo
Dai Maozheng
Ju Xiaoming
Zhang Xueping
Li Anping
Burbelo Peter
Stanley E Richard
Pestell Richard G
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.02124-05
Published
2006-06-00
Pages
4240-56
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1489104
Subset
IM
Grants
NCI NIH HHS · R01 CA075503 · United States
NCI NIH HHS · R01CA75503 · United States
NCI NIH HHS · P30 CA13330-31 · United States
NCI NIH HHS · R01 CA093596 · United States
NCI NIH HHS · R01CA93596 · United States
NCI NIH HHS · P30 CA56036 · United States
NCI NIH HHS · R37 CA026504 · United States
NCI NIH HHS · R01 CA070896 · United States
NCI NIH HHS · CA26504 · United States
NCI NIH HHS · R01CA107382 · United States
PHS HHS · P01 100324-02 · United States
NCI NIH HHS · R01CA70896 · United States
NCI NIH HHS · R01CA86072 · United States
NCI NIH HHS · R01 CA086072 · United States
NCI NIH HHS · P30 CA013330 · United States
NCI NIH HHS · R01 CA107382 · United States
NCI NIH HHS · R01 CA026504 · United States
NCI NIH HHS · P30 CA056036 · United States
External Links
PubMed source DOI: 10.1128/MCB.02124-05 PMC Full Text View journal details
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