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J. Biol. Chem., Vol. 279, Issue 30, 31948-31955, July 23, 2004

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Evidence for Cyclin D3 as a Novel Target of Rapamycin in Human T Lymphocytes^*

Marija Hleb, Shaun Murphy, Eric F. Wagner, Nazeeh N. Hanna, Nishant Sharma, Jungchen Park, Xian C. Li¶, Terry B. Strom, James F. Padbury, Yi-Tang Tseng, and Surendra Sharma||**

From the Departments of Pediatrics and ^||Pathology, Brown Medical School, Women and Infant's Hospital of Rhode Island, Providence, Rhode Island 02905 and the ^¶Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215

The immunosuppressant rapamycin has been shown to inhibit G₁/S transition of the cell cycle. This inhibition is thought to be mediated by maintenance of the threshold levels of cyclin-dependent kinase (CDK) inhibitor p27^Kip1 (p27) and inhibition of p70 s6 kinase (p70^s6k). However, recent evidence suggests that cells still remain sensitive to rapamycin in the absence of functional p27 or p70^s6k. Here, we show that rapamycin represses cyclin D3 levels in activated human T lymphocytes with no inhibitory effects on cyclin D2. Furthermore, rapamycin elicits similar cyclin D3 modulatory effects in B lymphocytes. The overall effect of rapamycin on cyclin D3 leads to impaired formation of active complexes with Cdk4 or Cdk6 and subsequent inhibition of cyclin D3/CDK kinase activity. Decrease in cyclin D3 protein levels is due to translational repression and not due to attenuated transcription of the cyclin D3 gene. Importantly, stable overexpression of cyclin D3 (2–2.5 fold) in Jurkat T cell transfectants renders them resistant to lower doses (1–10 ng/ml) of rapamycin. These results point to a critical role of cyclin D3 in rapamycin-mediated immunosuppressive effects in T cells and cell cycle regulation in lymphocytes in general.

Received for publication, January 20, 2004 , and in revised form, April 27, 2004.

^* This work was partly supported by funds from National Institutes of Health Grants COBRE in Perinatal Biology 1P20 RR018728-01 (to J. F. P., Y.-T. T., and S. S.), AI42298, and AI/GF41521; Juvenile Diabetes Foundation Grant 1-1999-16; and a Child Health Research grant from the Charles H. Hood Foundation (to Y.-T. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Bioscience and Biotechnology, Hankuk University of Foreign Studies, 89 Wangsan Mohyun, Yongin 499-791, Korea.

^** To whom correspondence should be addressed: Dept. of Pediatrics, 101 Dudley St., Providence, RI 02905. Tel.: 401-274-1122 (ext. 1289); Fax: 401-453-7571; E-mail: ssharma{at}wihri.org.

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