title: Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint.
abstract: Beta-catenin has been implicated in thymocyte development because of its function as a coactivator of Tcf/LEF-family transcription factors. Previously, we discovered a novel pathway for p53-induced beta-catenin degradation through a ubiquitin E3 ligase complex involving Siah1, SIP (CacyBP), Skp1, and Ebi. To gain insights into the physiological relevance of this new degradation pathway in vivo, we generated mutant mice lacking SIP. We demonstrate here that SIP-/- thymocytes have an impaired pre-TCR checkpoint with failure of TCRbeta gene rearrangement and increased apoptosis, resulting in reduced cellularity of the thymus. Moreover, the degradation of beta-catenin in response to DNA damage is significantly impaired in SIP-/- cells. SIP-/- embryonic fibroblasts show a growth-rate increase resulting from defects in G1 arrest. Thus, the beta-catenin degradation pathway mediated by SIP defines an essential checkpoint for thymocyte development and cell-cycle progression.
authors.affiliation: Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Toru
authors.initials: T
authors.lastname: Fukushima
authors.forename: Juan M
authors.initials: JM
authors.lastname: Zapata
authors.forename: Netai C
authors.initials: NC
authors.lastname: Singha
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Christina L
authors.initials: CL
authors.lastname: Kress
authors.forename: Maryla
authors.initials: M
authors.lastname: Krajewska
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Ronai
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Shu-Ichi
authors.initials: S
authors.lastname: Matsuzawa
mesh_terms: D000818:Animals; D017209:Apoptosis; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D016193:G1 Phase / Q000235:genetics; D005720:Gamma Rays; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis; D009929:Organ Size; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000254:growth & development; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000528:radiation effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C111922:Cacybp protein, mouse; D002135:Calcium-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases