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

研究成果: Article査読

104 被引用数 (Scopus)


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.

ジャーナルGenes and Development
出版ステータスPublished - 2013 5月 15

ASJC Scopus subject areas

  • 医学(全般)


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