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Molecular and Cellular Biology, July 2004, p. 6205-6214, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6205-6214.2004

Rac1 Inhibits Apoptosis in Human Lymphoma Cells by Stimulating Bad Phosphorylation on Ser-75

Baolin Zhang,* Yaqin Zhang, and Emily Shacter

Laboratory of Biochemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892

Received 26 November 2003/ Returned for modification 8 January 2004/ Accepted 23 April 2004

The small GTPase Rac1 has emerged as an important regulator of cell survival and apoptosis, but the mechanisms involved are not completely understood. In this report, constitutively active Rac1 is shown to stimulate the phosphorylation of the Bcl-2 family member Bad, thereby suppressing drug-induced caspase activation and apoptosis in human lymphoma cells. Rac1 activation leads to human Bad phosphorylation specifically at serine-75 (corresponding to murine serine-112) both in vivo and in vitro. Inhibition of constitutive and activated Rac1-induced Bad phosphorylation by a cell-permeable competitive peptide inhibitor representing this Bad phosphorylation site sensitizes lymphoma cells to drug-induced apoptosis. The data show further that endogenous protein kinase A is a primary catalyst of cellular Bad phosphorylation in response to Rac activation, while Akt is not involved. These findings define a mechanism by which active Rac1 promotes lymphoma cell survival and inhibits apoptosis in response to cancer chemotherapy drugs.

* Corresponding author. Mailing address: Laboratory of Biochemistry, FDA/CDER, 29 Lincoln Dr., Bldg. 29A, Rm. 2B-24, Bethesda, MD 20892-4555. Phone: (301) 827-1784. Fax: (301) 480-3256. E-mail: baolin.zhang{at}fda.gov.

Molecular and Cellular Biology, July 2004, p. 6205-6214, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6205-6214.2004




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