Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells.

Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells. Research Abstract Details 

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Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells. Abstract Text:

Louise Westbrook,Marina Manuvakhova,Francis G Kern,Norman R Estes,Harish N Ramanathan,Jaideep V Thottassery,Louise Westbrook,Marina Manuvakhova,Francis G Kern,Norman R Estes,Harish N Ramanathan,Jaideep V Thottassery,

Cks1, a small protein whose expression is strongly associated with aggressive breast tumors, is a component of cyclin-cdk complexes, as well as the SCF(Skp2) ubiquitin ligase. In these studies, we explored its roles in estrogen receptor-positive breast tumor cells. When exposed to the antiestrogen ICI 182780, these cells accumulate in G(1) by reducing the expression of Cks1, and increasing the levels of p130/Rb2, a cdk2 inhibitor and SCF(Skp2) target. Heregulin beta1 or estradiol abrogate antiestrogen effects by increasing Cks1 expression, down-regulating p130/Rb2 and inducing S phase entry. Depletion of Cks1 in these cells by RNA interference concomitantly decreased Skp2 and up-regulated p130/Rb2 and another SCF(Skp2) target, p27(Kip1). Remarkably, however, Cks1-depleted cells not only exhibit slowed G(1) progression, but also accumulate in G(2)-M due to blocked mitotic entry. Notably, we show that cdk1 expression, which is crucial for M phase entry, is drastically diminished by Cks1 depletion, and that restoration of cdk1 reduces G(2)-M accumulation in Cks1-depleted cells. cdk1 reduction in Cks1-depleted cells is a consequence of a marked decrease in its mRNA and not due to alteration in its proteolytic turnover. Both heregulin beta1 and estradiol could neither restore cdk1 nor sustain cycling in Cks1-depleted cells, although classical estrogen receptor function remained unaltered. Cks1 depletion also decreased Skp2 in human mammary epithelial cells without altering cell cycle progression. Thus, the indispensability of Cks1 to the breast cancer cell cycle, versus its redundancy in normal cells, suggests that Cks1 abrogation could be an effective interventional strategy in breast cancer.

Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells. Publishing Authors By Initials

L Westbrook,M Manuvakhova,FG Kern,NR Estes,HN Ramanathan,JV Thottassery,L Westbrook,M Manuvakhova,FG Kern,NR Estes,HN Ramanathan,JV Thottassery,

For similar proteins: carrier proteins: s-phase kinase-associated proteins research abstracts see: proteins: carrier proteins: s-phase kinase-associated proteins research

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Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Cancer research

VOLUME: 67

Page Numbers: 11393-401

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 1

MONTH: Dec

YEAR: 2007

Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells. Keywords Mesh Terms:

KEYWORDS: S-Phase Kinase-Associated Proteins

MESH TERMS: metabolism

Chemical & Substance for Abstract: Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells. Information

Substance Name: Cyclin-Dependent Kinases

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for Cks1 regulates cdk1 expression: a novel role during mitotic entry in breast cancer cells.

AFFILIATION: Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA50376

ACRONYM: CA

MEDLINETA: Cancer Res

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