Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint.
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.
Fukushima
Toru
T
Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
Zapata
Juan M
JM
Singha
Netai C
NC
Thomas
Michael
M
Kress
Christina L
CL
Krajewska
Maryla
M
Krajewski
Stan
S
Ronai
Ze'ev
Z
Reed
John C
JC
Matsuzawa
Shu-Ichi
S
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*
C111922:Cacybp protein, mouse; D002135:Calcium-Binding Proteins; D011948:Receptors, Antigen, T-Cell; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases