Constitutive phosphorylation mutation in Fas-associated death domain (FADD) results in early cell cycle defects.
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 G(0) and G(1) 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.
Osborn
Stephanie L
SL
Cancer Research Laboratory and Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720-3200, USA.
Sohn
Sue J
SJ
Winoto
Astar
A
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D053200:Fas-Associated Death Domain Protein / Q000737:chemistry* / Q000235:genetics*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D010766:Phosphorylation; D053218:Receptors, Death Domain / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism
D053200:Fas-Associated Death Domain Protein; D053218:Receptors, Death Domain; D016160:Retinoblastoma Protein