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J. Biol. Chem., Vol. 280, Issue 35, 30723-30734, September 2, 2005

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Schlafen-1 Causes a Cell Cycle Arrest by Inhibiting Induction of Cyclin D1^*

Gareth Brady, Louise Boggan, Andrew Bowie, and Luke A. J. O'Neill

From the School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland

Schlafen-1 (Slfn-1), the prototypic member of the Schlafen family of proteins, was described as an inducer of growth arrest in T-lymphocytes and causes a cell cycle arrest in NIH3T3 fibroblasts prior to the G₁/S transition. How Slfn-1 exerts its effects on the cell cycle is not currently known. We report that synchronized murine fibroblasts expressing Slfn-1 do not exit G₁ when stimulated with fetal calf serum, platelet-derived growth factor BB (PDGF-BB) or epidermal growth factor (EGF). The induction of cyclin D1 by these stimuli was blocked in the presence of Slfn-1 as were all downstream cell cycle processes. Overexpression of cyclin D1 in growth-arrested, Slfn-1-expressing cells induced an increase in cell growth consistent with this protein being the biological target of Slfn-1. Activation of the mitogen-activated protein kinase pathway by EGF or phorbol 12-myristate 13-acetate was unaffected by Slfn-1 expression. PDGF signaling was, however, almost completely blocked. This was due to a lack of PDGF receptor expression in Slfn-1-expressing cells consistent with Slfn-1 blocking the cell cycle in G₁ where PDGF receptor expression is normally down-regulated. Finally, overexpression of Slfn-1 inhibited the activation of the cyclin D1 promoter. Slfn-1 therefore causes a cell cycle arrest during G₁ by inhibiting induction of cyclin D1 by mitogens.

Received for publication, January 13, 2005 , and in revised form, May 24, 2005.

^* This work was supported by the Higher Education Authority, Grant PRTL3, and Science Foundation Ireland. 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.

To whom correspondence should be addressed: Cytokine Research Laboratory, School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland. Tel.: 353-1-608-2449; Fax: 353-1-677-2400; E-mail: bradyg1{at}tcd.ie.

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