Liu J, Stevens J, Rote C A, Yost H J, Hu Y, Neufeld K L, White R L, Matsunami N
Department of Oncological Sciences, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
Mol Cell. 2001 May;7(5):927-36. doi: 10.1016/s1097-2765(01)00241-6.
The adenomatous polyposis coli (APC) tumor-suppressor protein, together with Axin and GSK3beta, forms a Wnt-regulated signaling complex that mediates phosphorylation-dependent degradation of beta-catenin by the proteasome. Siah-1, the human homolog of Drosophila seven in absentia, is a p53-inducible mediator of cell cycle arrest, tumor suppression, and apoptosis. We have now found that Siah-1 interacts with the carboxyl terminus of APC and promotes degradation of beta-catenin in mammalian cells. The ability of Siah-1 to downregulate beta-catenin signaling was also demonstrated by hypodorsalization of Xenopus embryos. Unexpectedly, degradation of beta-catenin by Siah-1 was independent of GSK3beta-mediated phosphorylation and did not require the F box protein beta-TrCP. These results indicate that APC and Siah-1 mediate a novel beta-catenin degradation pathway linking p53 activation to cell cycle control.
腺瘤性结肠息肉病蛋白（APC）肿瘤抑制蛋白与Axin和糖原合成酶激酶3β（GSK3β）共同形成一种受Wnt调节的信号复合物，该复合物介导蛋白酶体对β-连环蛋白进行磷酸化依赖性降解。Siah-1是果蝇“七缺失”蛋白的人类同源物，是一种p53诱导的细胞周期停滞、肿瘤抑制和凋亡的介质。我们现在发现，Siah-1与APC的羧基末端相互作用，并促进哺乳动物细胞中β-连环蛋白的降解。非洲爪蟾胚胎的背部化也证明了Siah-1下调β-连环蛋白信号的能力。出乎意料的是，Siah-1介导的β-连环蛋白降解不依赖于GSK3β介导的磷酸化，也不需要F盒蛋白β-TrCP。这些结果表明，APC和Siah-1介导了一条将p53激活与细胞周期控制联系起来的新的β-连环蛋白降解途径。
