Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates beta-catenin activity in a p53-dependent manner.
Beta-catenin is a potent oncogenic protein whose cytoplasmic accumulation is a frequent event in cancer cells. The level of beta-catenin is regulated by two mechanisms: the adenomatous polyposis coli/Axin/glycogen synthase kinase 3beta-dependent degradation pathway and the Siah-1/Siah interacting protein/Ebi-mediated degradation pathway. In this study, we have investigated the functional significance of p53-inducible human Siah-family protein expression in the regulation of beta-catenin activity. We show here by reverse-transcriptase polymerase chain reaction that two mRNA transcripts, designated human Siah-1 and Siah-1L, are generated from the human Siah-1 locus. Interestingly, the expression of Siah-1L was upregulated by p53, whereas human Siah-1 expression was constant. Furthermore, introduction of exogenous Siah-1L protein downregulated beta-catenin protein and promoted apoptosis induced by anticancer drugs in cancer cells that lack endogenous p53. Thus, Siah-1L represents a new member of the human Siah family that is induced in response to p53 and plays an important role in the regulation of beta-catenin activity in tumor cells. These findings also suggest new strategies for restoring tumor suppressive pathways lost in cancer cells that have suffered p53 inactivation.
Iwai
Akio
A
Division of Gastroenterology and Hepatology, Department of Medicine, Kyoto University, Japan.
Marusawa
Hiroyuki
H
Matsuzawa
Shu-ichi
S
Fukushima
Toru
T
Hijikata
Makoto
M
Reed
John C
JC
Shimotohno
Kunitada
K
Chiba
Tsutomu
T
D001483:Base Sequence; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017931:DNA Primers; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000502:physiology; D051176:beta Catenin; D000098563:Seven in Absentia Proteins
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D009687:Nuclear Proteins; D011506:Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins