This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Westbrook, L. Articles by Thottassery, J. V. Search for Related Content PubMed PubMed Citation Articles by Westbrook, L. Articles by Thottassery, J. V.

Cks1 Regulates cdk1 Expression: A Novel Role during Mitotic Entry in Breast Cancer Cells

¹ Southern Research Institute and ² University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, Alabama

Requests for reprints: Jaideep Thottassery, Biochemistry and Molecular Biology Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205. Phone: 205-581-2846; Fax: 205-581-2877; E-mail: thottassery{at}sri.org.

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 G₁ by reducing the expression of Cks1, and increasing the levels of p130/Rb2, a cdk2 inhibitor and SCF^Skp2 target. Heregulin β1 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 G₁ progression, but also accumulate in G₂-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 G₂-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 β1 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. [Cancer Res 2007;67(23):11393–401]

This article has been cited by other articles:

				M. Radulovic, E. Crane, M. Crawford, J. Godovac-Zimmermann, and V. P. C. C. Yu CKS Proteins Protect Mitochondrial Genome Integrity by Interacting with Mitochondrial Single-stranded DNA-binding Protein Mol. Cell. Proteomics, January 1, 2010; 9(1): 145 - 152. [Abstract] [Full Text] [PDF]