Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15
- Satoshi Inoue1,
- Zhenyue Hao1,
- Andrew J. Elia1,
- David Cescon1,
- Lily Zhou1,
- Jennifer Silvester1,
- Bryan Snow1,
- Isaac S. Harris1,
- Masato Sasaki1,
- Wanda Y. Li1,
- Momoe Itsumi1,
- Kazuo Yamamoto1,
- Takeshi Ueda1,
- Carmen Dominguez-Brauer1,
- Chiara Gorrini1,
- Iok In Christine Chio1,
- Jillian Haight1,
- Annick You-Ten1,
- Susan McCracken1,
- Andrew Wakeham1,
- Danny Ghazarian2,
- Linda J.Z. Penn1,3,
- Gerry Melino4,5 and
- Tak W. Mak1,6
- 1The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada;
- 2Department of Laboratory of Medicine and Pathology, University of Toronto, University Health Network, Toronto, Ontario M5G 2M9, Canada;
- 3Department of Medical Biophysics, University of Toronto, University Health Network, Toronto, Ontario M5G 2M9, Canada;
- 4Medical Research Council, Toxicology Unit, Leicester LE1 9HN, United Kingdom;
- 5Department of Experimental Medicine and Surgery, Biochemistry IDI-IRCCS Laboratory, University of Rome “Tor Vergata,” Rome 00133, Italy
Abstract
Tumorigenesis results from dysregulation of oncogenes and tumor suppressors that influence cellular proliferation, differentiation, apoptosis, and/or senescence. Many gene products involved in these processes are substrates of the E3 ubiquitin ligase Mule/Huwe1/Arf-BP1 (Mule), but whether Mule acts as an oncogene or tumor suppressor in vivo remains controversial. We generated K14Cre;Muleflox/flox(y) (Mule kKO) mice and subjected them to DMBA/PMA-induced skin carcinogenesis, which depends on oncogenic Ras signaling. Mule deficiency resulted in increased penetrance, number, and severity of skin tumors, which could be reversed by concomitant genetic knockout of c-Myc but not by knockout of p53 or p19Arf. Notably, in the absence of Mule, c-Myc/Miz1 transcriptional complexes accumulated, and levels of p21CDKN1A (p21) and p15INK4B (p15) were down-regulated. In vitro, Mule-deficient primary keratinocytes exhibited increased proliferation that could be reversed by Miz1 knockdown. Transfer of Mule-deficient transformed cells to nude mice resulted in enhanced tumor growth that again could be abrogated by Miz1 knockdown. Our data demonstrate in vivo that Mule suppresses Ras-mediated tumorigenesis by preventing an accumulation of c-Myc/Miz1 complexes that mediates p21 and p15 down-regulation.
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Footnotes
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↵6 Corresponding author
E-mail tmak{at}uhnres.utoronto.ca
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.214577.113.
- Received January 23, 2013.
- Accepted April 23, 2013.
- Copyright © 2013 by Cold Spring Harbor Laboratory Press
Freely available online through the Genes & Development Open Access option.