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Abstract
14-3-3 proteins regulate many cellular functions, including proliferation. However, the detailed mechanisms by which they control the cell cycle remain to be fully elucidated. We report that one of the 14-3-3 isoforms, 14-3-3τ, is required for the G1/S transition through its role in ubiquitin-independent proteasomal degradation of p21. 14-3-3τ binds to p21, MDM2, and the C8 subunit of the 20S proteasome in G1 phase and facilitates proteasomal targeting of p21. This function of 14-3-3τ may be deregulated in cancer. The overexpression of 14-3-3τ is frequently found in primary human breast cancer and correlates with lower levels of p21 and shorter patient survival. Tenascin-C, an extracellular matrix protein involved in tumor initiation and progression and a known 14-3-3τ inducer, decreases p21 and abrogates adriamycin-induced G1/S arrest. It has been known that p21 is required for a proper tamoxifen response in breast cancer. We show that the overexpression of 14-3-3τ inhibits tamoxifen-induced p21 induction and growth arrest in MCF7 cells. Together, the findings of our studies strongly suggest a novel oncogenic role of 14-3-3τ by downregulating p21 in breast cancer. Therefore, 14-3-3τ may be a potential therapeutic target in breast cancer.
Supplemental material for this article may be found at http://mcb.asm.org/.
We gratefully acknowledge the UAB Tissue Procurement Facility for providing breast tumor specimens, Stephen W. Michnick for the YFP1 and YFP2 vectors, Wafik El-Deiry for pCEP-p21, Martin Allday and Ruiwen Zhang for GST-C8, Kei-ichi Nakayama for sibling-matched primary Skp2+/+ and Skp2−/− MEFs, Bert Vogelstein for p53+/+ and p53−/− HCT116 cells and p21+/+ and p21−/− HCT116 cells, and James Ou for ts85 cells. We also thank Fannie Lin for valuable discussions and reagents.
The work was supported by grants from NIH (CA 100857) and the U.S. Department of Defense Breast Cancer Research Program (grant W81XWH-09-1-0338). W.-C.L. is a Leukemia and Lymphoma Society scholar.
We all disclose that we have no financial interests that will pose a conflict of interest regarding the work reported in this article.