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  • Oncogenomics
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Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates β-catenin activity in a p53-dependent manner

Oncogene volume 23, pages 7593–7600 (2004)Cite this article

Abstract

β-Catenin is a potent oncogenic protein whose cytoplasmic accumulation is a frequent event in cancer cells. The level of β-catenin is regulated by two mechanisms: the adenomatous polyposis coli/Axin/glycogen synthase kinase 3β-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 β-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 β-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 β-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.

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Abbreviations

APC:

adenomatous polyposis coli

GSK3β:

glycogen synthase kinase 3β

SIP:

Siah interacting protein

HCC:

hepatocellular carcinoma

RT–PCR:

reverse-transcriptase polymerase chain reaction

DOX:

doxorubicin

siRNA:

short interfering RNA

Tcf:

T-cell factors

LEF:

lymphocyte enhancer-binding factor

SDS–PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

TK:

thymidine kinase

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Acknowledgements

This work was supported by grants-in-aid for cancer research and for the second-term comprehensive 10-year strategy for cancer control and the Ministry of Health, Labor, and Welfare, through grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology, grants-in-aid of Research for the Future from the Japanese Society for the Promotion of Science, and by the Program for Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (OPSR) of Japan.

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, Kyoto University, Kyoto, Japan

    Akio Iwai, Hiroyuki Marusawa, Toru Fukushima & Tsutomu Chiba

  2. Department of Viral Oncology, Laboratory of Human Tumor Viruses, Institute for Virus Research, Kyoto University, Kyoto, Japan

    Akio Iwai, Makoto Hijikata & Kunitada Shimotohno

  3. The Burnham Institute, La Jolla, 92037, CA, USA

    Shu-ichi Matsuzawa, Toru Fukushima & John C Reed

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  1. Akio Iwai
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  2. Hiroyuki Marusawa
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Correspondence to Kunitada Shimotohno.

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Iwai, A., Marusawa, H., Matsuzawa, Si. et al. Siah-1L, a novel transcript variant belonging to the human Siah family of proteins, regulates β-catenin activity in a p53-dependent manner. Oncogene 23, 7593–7600 (2004). https://doi.org/10.1038/sj.onc.1208016

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