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J. Biol. Chem., Vol. 282, Issue 31, 22786-22792, August 3, 2007

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Constitutive Phosphorylation Mutation in Fas-associated Death Domain (FADD) Results in Early Cell Cycle Defects^*

From the Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720-3200

Fas-associated death domain (FADD) is an adaptor molecule for the death receptor subfamily of the tumor necrosis factor receptor superfamily, but it is also required for cell proliferation. Cell cycle-specific regulation of FADD phosphorylation plays an important role in FADD proliferative function since mice with a mutant form of FADD mimicking constitutive phosphorylation at serine 191 (FADD-D) exhibit defective T cell proliferation. Here we characterized these mice in detail and found that T cell development in 2-4-week-old mice is relatively normal, although mature FADD-D T cells manifest defective G₀ and G₁ to S transition with abnormalities in regulation of p130, p27 degradation, retinoblastoma protein phosphorylation, and CDK2 kinase activity. These downstream defects are further associated with the failure to up-regulate the forkhead box M1 cell cycle transcription factor, FoxM1. FADD-D protein is also mislocalized during cell cycle progression. Thus, regulation of FADD phosphorylation is crucial for proper cell cycle entry.

Received for publication, April 16, 2007 , and in revised form, May 11, 2007.

^* This work is supported by a grant from the National Institute of Health (to A. W.). 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.

¹ To whom correspondence should be addressed: Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California Berkeley, 465 LSA, Berkeley, CA 94720-3200. E-mail: winoto{at}berkeley.edu.

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