In vitro soft agar assays showed that SIAH1S promoted cell tumorigenicity. SIAH1S had a dominant-negative effect on SIAH1, as only SIAH1 homodimers, but not SIAH1S homodimers or SIAH1-SIAH1S heterodimers, could bind SIP and degrade beta-catenin.

SIAH1S upregulated beta-catenin-dependent TCF/LEF transcriptional activation in a human breast cancer cell line and antagonized SIAH1-mediated potentiation of etoposide-induced apoptosis. (2007) found that SIAH1S had an even shorter half-life than SIAH1 and could catalyze self-ubiquitination that resulted in its subsequent degradation by the proteasome. These results indicated that APC and SIAH1 mediate a beta-catenin degradation pathway linking p53 activation to cell cycle control. Unexpectedly, degradation of beta-catenin by SIAH1 was independent of glycogen synthase kinase 3-beta ( 605004)-mediated phosphorylation and did not require the F-box protein BTRC ( 603482). The ability of SIAH1 to downregulate beta-catenin signaling was also demonstrated by hypodorsalization of Xenopus embryos. (2001) found that SIAH1 interacts with the C terminus of the adenomatous polyposis coli protein (APC 611731) and promotes degradation of beta-catenin in mammalian cells. SIAH1 is physically linked to EBI by association with SIP, which binds SKP1. This pathway is inducible by p53 ( 191170), revealing a link between genotoxic injury responses and beta-catenin degradation. Matsuzawa and Reed (2001) elucidated a network of protein interactions in which SIAH1, SIP ( 606186), SKP1 ( 601434), and EBI ( 300196) collaborate in a pathway controlling beta-catenin ( 116806) levels, affecting activity of beta-catenin-dependent TCF (e.g., TCF1 142410) and LEF (e.g., LEF1 153245) transcription factors. Furthermore, given the role of sina in Drosophila photoreceptor development, SIAH2 was considered a candidate for the Usher syndrome type 3 ( 276902) gene, which maps to 3q21-q25. Their substantial evolutionary conservation, role in specifying cell fate, and activation in apoptotic cells suggested that the SIAH proteins have important roles in vertebrate development. While a previous study suggested that sina is a nuclear protein, epitope-labeled sina and SIAH1 proteins were found in the cytoplasm of Drosophila and mammalian cells. However, 1 of 3 murine homologs, Siah1b, was strongly induced in fibroblasts undergoing apoptotic cell death. (1997) found that SIAH1 and SIAH2 are expressed in many normal and neoplastic tissues, and only subtle differences in their expression were noted.

Half life e3 1997