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

• Published in: Genes & development 2013-05, Vol.27 (10), p.1101-1114
• Main Authors: Inoue, Satoshi, Hao, Zhenyue, Elia, Andrew J, Cescon, David, Zhou, Lily, Silvester, Jennifer, Snow, Bryan, Harris, Isaac S, Sasaki, Masato, Li, Wanda Y, Itsumi, Momoe, Yamamoto, Kazuo, Ueda, Takeshi, Dominguez-Brauer, Carmen, Gorrini, Chiara, Chio, Iok In Christine, Haight, Jillian, You-Ten, Annick, McCracken, Susan, Wakeham, Andrew, Ghazarian, Danny, Penn, Linda J Z, Melino, Gerry, Mak, Tak W
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - pharmacology; Animals; Cell Transformation, Neoplastic - genetics; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p15 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p15 - genetics; Cyclin-Dependent Kinase Inhibitor p15 - metabolism; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Down-Regulation; Female; Genes, ras; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - pathology; Male; Mice; Mice, Knockout; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - deficiency; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncogene Protein p21(ras) - antagonists & inhibitors; Oncogene Protein p21(ras) - genetics; Oncogene Protein p21(ras) - metabolism; Protein Inhibitors of Activated STAT - antagonists & inhibitors; Protein Inhibitors of Activated STAT - deficiency; Protein Inhibitors of Activated STAT - genetics; Protein Inhibitors of Activated STAT - metabolism; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - deficiency; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Research Paper; Signal Transduction; Skin Neoplasms - chemically induced; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tetradecanoylphorbol Acetate - pharmacology; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.214577.113

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;Mule(flox/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.