Siah-1S, a novel splice variant of Siah-1 (seven in absentia homolog), counteracts Siah-1-mediated downregulation of beta-catenin.
Siah-1 (seven in absentia homolog) is known to cause indirect degradation of beta-catenin through formation of a complex with Siah-interacting protein (SIP), Skp1 and Ebi. Here, we report the characterization of a novel splice variant of human Siah-1, designated Siah-1S, which is produced by an alternative splicing mechanism. The novel intron/exon junctions used to generate Siah-1S follow a non-conventional CT-AC rule. Siah-1S exhibits an even shorter half-life than Siah-1 and is able to catalyse self-ubiquitination that results in its subsequent degradation by proteasome. Siah-1S is shown to upregulate beta-catenin-dependent Tcf/Lef transcriptional activation and antagonize Siah-1's potentiation effect on the apoptosis induced by etoposide in MCF-7 cells. Additionally, Siah-1S is found to interact with Siah-1 to form heterodimer or with itself to form homodimer. Unlike homodimer Siah-1*Siah-1, neither Siah-1*Siah-1S nor Siah-1S*Siah-1S is able to bind to Siah-1-interacting protein, which may explain the underlying mechanism for Siah-1S's dominant negative effect on Siah-1. Importantly, results from in vitro soft agar assay demonstrated that Siah-1S displays a promotion effect on cells tumorigenicity.
Mei
Y
Y
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, PR China.
Xie
C
C
Xie
W
W
Wu
Z
Z
Wu
M
M
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D015536:Down-Regulation; D005047:Etoposide / Q000494:pharmacology; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D015854:Up-Regulation; D051176:beta Catenin / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
C491778:CACYBP protein, human; D002135:Calcium-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D025801:Ubiquitin; D051176:beta Catenin; D005047:Etoposide; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D046988:Proteasome Endopeptidase Complex