Schlafen-1 causes a cell cycle arrest by inhibiting induction of cyclin D1

Schlafen- 1 ( Slfn- 1), the prototypic member of the family of proteins, was described as an inducer growth arrest in T- lymphocytes and causes a cell cycle in NIH3T3 fibroblasts prior to the G(1)/ S transition. 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 G(1) when stimulated 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. of cyclin D1 in growth- arrested, Slfn- 1cells induced an increase in cell growth consistent with this protein being the biological target of 1. Activation of the mitogen- activated protein kinase by EGF or phorbol 12- myristate 13- acetate was by Slfn- 1 expression. PDGF signaling was, almost completely blocked. This was due to a of PDGF receptor expression in Slfn- 1- expressing consistent with Slfn- 1 blocking the cell cycle in G1 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 cycle arrest during G1 by inhibiting induction of cyclin D1 by mitogens.