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

被引：51

作者：

Fukushima, T ^{[1
]}

Zapata, JM ^{[1
]}

Singha, NC ^{[1
]}

Thomas, M ^{[1
]}

Kress, CL ^{[1
]}

Krajewska, M ^{[1
]}

Krajewski, S ^{[1
]}

Ronai, Z ^{[1
]}

Reed, JC ^{[1
]}

Matsuzawa, S ^{[1
]}

机构：

[1] Burnham Inst Med Res, La Jolla, CA 92037 USA

来源：

IMMUNITY | 2006年 / 24卷 / 01期

关键词：

D O I：

10.1016/j.immuni.2005.12.002

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

b-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 TCR beta 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.

引用

页码：29 / 39

页数：11

共 58 条

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