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.
Division of Gastroenterology and Hepatology, Department of Medicine, Kyoto University, Japan.
Akio
A
Iwai
Hiroyuki
H
Marusawa
Shu-ichi
S
Matsuzawa
Toru
T
Fukushima
Makoto
M
Hijikata
John C
JC
Reed
Kunitada
K
Shimotohno
Tsutomu
T
Chiba
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