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Dynein Light Chain 1 Contributes to Cell Cycle Progression by Increasing Cyclin-Dependent Kinase 2 Activity in Estrogen-Stimulated Cells

Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center and The University of Texas School of Biomedical Sciences at Houston Program of Cancer Biology, Houston, Texas

Requests for reprints: Rakesh Kumar, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-745-3558; Fax: 713-745-3792; E-mail: rkumar{at}mdanderson.org.

Progression of hormone-responsive cancers is characterized by deregulation of the cell cycle and cytoskeleton signaling. In addition, development of breast and endometrial cancer is influenced by the stimulatory action of estrogen. Up-regulation of dynein light chain 1 (DLC1), a component of cytoskeleton signaling, was recently found to promote tumorigenesis. The purpose of our study was to determine the role that DLC1 up-regulation plays in cell cycle progression. To achieve this goal, we used human breast ductal carcinoma ZR-75 cells overexpressing DLC1 as a model system. We found that ZR-75 cells with up-regulated DLC1 were hypersensitive to estrogen-dependent growth stimulation and that DLC1 had an accelerating effect on the G₁-S transition and stimulated cyclin-dependent kinase 2 (Cdk2) activity. To better understand the promotion of the G₁-S transition by DLC1, we sought to identify new DLC1-interacting proteins with roles in cell cycle regulation. Using a modified proteomic strategy, we identified two such DLC1-interacting proteins: Cdk2 and Cip-interacting zinc finger protein 1 (Ciz1). DLC1 was verified to interact with Cdk2 and Ciz1 in vivo. We also showed that down-regulation of DLC1 and Ciz1 reduced both Cdk2 activity and cell cycle progression of breast cancer ZR-75 and MCF-7 and endometrial Ishikawa cancer cells. Further, we showed that overexpression of DLC1 is accompanied by a reduction of nuclear p21^WAF1. These findings suggest that interactions among DLC1, Cdk2, and Ciz1 play a regulatory role in cell cycle progression of cancer cells presumably by influencing the levels of nuclear p21^WAF1. (Cancer Res 2006; 66(11): 5941-9)

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