Critical function for SIP, a ubiquitin E3 ligase component of the β-catenin degradation pathway, for thymocyte development and G1 checkpoint

Toru Fukushima, Juan M. Zapata, Netai C. Singha, Michael Thomas, Christina L. Kress, Maryla Krajewska, Stan Krajewski, Ze'ev Ronai, John C. Reed, Shu Ichi Matsuzawa

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

β-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 β-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 TCRβ gene rearrangement and increased apoptosis, resulting in reduced cellularity of the thymus. Moreover, the degradation of β-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 β-catenin degradation pathway mediated by SIP defines an essential checkpoint for thymocyte development and cell-cycle progression.

Original languageEnglish
Pages (from-to)29-39
Number of pages11
JournalImmunity
Volume24
Issue number1
DOIs
StatePublished - Jan 2006
Externally publishedYes

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