Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15

Satoshi Inoue, Zhenyue Hao, Andrew J. Elia, David Cescon, Lily Zhou, Jennifer Silvester, Bryan Snow, Isaac S. Harris, Masato Sasaki, Wanda Y. Li, Momoe Itsumi, Kazuo Yamamoto, Takeshi Ueda, Carmen Dominguez-Brauer, Chiara Gorrini, Iok In Christine Chio, Jillian Haight, Annick You-Ten, Susan McCracken, Andrew WakehamDanny Ghazarian, Linda J Z Penn, Gerry Melino, Tak W. Mak

Research output: Contribution to journalArticle

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/PMAinduced 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, Muledeficient 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.

Original languageEnglish
Pages (from-to)1101-1114
Number of pages14
JournalGenes and Development
Volume27
Issue number10
DOIs
Publication statusPublished - May 15 2013

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Keywords

  • c-Myc
  • Huwe1
  • Miz1
  • Mule
  • p21
  • Ras

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Inoue, S., Hao, Z., Elia, A. J., Cescon, D., Zhou, L., Silvester, J., Snow, B., Harris, I. S., Sasaki, M., Li, W. Y., Itsumi, M., Yamamoto, K., Ueda, T., Dominguez-Brauer, C., Gorrini, C., Christine Chio, I. I., Haight, J., You-Ten, A., McCracken, S., ... Mak, T. W. (2013). Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15. Genes and Development, 27(10), 1101-1114. https://doi.org/10.1101/gad.214577.113