title: Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15.
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;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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Elia
authors.forename: David
authors.initials: D
authors.lastname: Cescon
authors.forename: Lily
authors.initials: L
authors.lastname: Zhou
authors.forename: Jennifer
authors.initials: J
authors.lastname: Silvester
authors.forename: Bryan
authors.initials: B
authors.lastname: Snow
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Harris
authors.forename: Masato
authors.initials: M
authors.lastname: Sasaki
authors.forename: Wanda Y
authors.initials: WY
authors.lastname: Li
authors.forename: Momoe
authors.initials: M
authors.lastname: Itsumi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.forename: Carmen
authors.initials: C
authors.lastname: Dominguez-Brauer
authors.forename: Chiara
authors.initials: C
authors.lastname: Gorrini
authors.forename: Iok In Christine
authors.initials: II
authors.lastname: Chio
authors.forename: Jillian
authors.initials: J
authors.lastname: Haight
authors.forename: Annick
authors.initials: A
authors.lastname: You-Ten
authors.forename: Susan
authors.initials: S
authors.lastname: McCracken
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.forename: Danny
authors.initials: D
authors.lastname: Ghazarian
authors.forename: Linda J Z
authors.initials: LJ
authors.lastname: Penn
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D011905:Genes, ras; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050828:Protein Inhibitors of Activated STAT / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; C502831:Huwe1 protein, mouse; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D015689:Oncogene Protein p21(ras); D013755:Tetradecanoylphorbol Acetate
keywords: Huwe1; Miz1; Mule; Ras; c-Myc; p21