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

71 Citations (Scopus)

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

Fingerprint

Equidae
Carcinogenesis
Down-Regulation
Oncogenes
Neoplasms
9,10-Dimethyl-1,2-benzanthracene
Skin
Ubiquitin-Protein Ligases
Penetrance
Keratinocytes
Nude Mice
Cell Proliferation
Apoptosis
Growth

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15. / 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; Christine Chio, Iok In; Haight, Jillian; You-Ten, Annick; McCracken, Susan; Wakeham, Andrew; Ghazarian, Danny; Penn, Linda J Z; Melino, Gerry; Mak, Tak W.

In: Genes and Development, Vol. 27, No. 10, 15.05.2013, p. 1101-1114.

Research output: Contribution to journalArticle

Inoue, S, Hao, Z, Elia, AJ, Cescon, D, Zhou, L, Silvester, J, Snow, B, Harris, IS, Sasaki, M, Li, WY, Itsumi, M, Yamamoto, K, Ueda, T, Dominguez-Brauer, C, Gorrini, C, Christine Chio, II, Haight, J, You-Ten, A, McCracken, S, Wakeham, A, Ghazarian, D, Penn, LJZ, Melino, G & Mak, TW 2013, 'Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15', Genes and Development, vol. 27, no. 10, pp. 1101-1114. https://doi.org/10.1101/gad.214577.113
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 ; Christine Chio, Iok In ; Haight, Jillian ; You-Ten, Annick ; McCracken, Susan ; Wakeham, Andrew ; Ghazarian, Danny ; Penn, Linda J Z ; Melino, Gerry ; Mak, Tak W. / Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15. In: Genes and Development. 2013 ; Vol. 27, No. 10. pp. 1101-1114.
@article{873a48eaef8e4fb6ba6d872e56bf69f5,
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;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.",
keywords = "c-Myc, Huwe1, Miz1, Mule, p21, Ras",
author = "Satoshi Inoue and Zhenyue Hao and Elia, {Andrew J.} and David Cescon and Lily Zhou and Jennifer Silvester and Bryan Snow and Harris, {Isaac S.} and Masato Sasaki and Li, {Wanda Y.} and Momoe Itsumi and Kazuo Yamamoto and Takeshi Ueda and Carmen Dominguez-Brauer and Chiara Gorrini and {Christine Chio}, {Iok In} and Jillian Haight and Annick You-Ten and Susan McCracken and Andrew Wakeham and Danny Ghazarian and Penn, {Linda J Z} and Gerry Melino and Mak, {Tak W.}",
year = "2013",
month = "5",
day = "15",
doi = "10.1101/gad.214577.113",
language = "English",
volume = "27",
pages = "1101--1114",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "10",

}

TY - JOUR

T1 - Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15

AU - Inoue, Satoshi

AU - Hao, Zhenyue

AU - Elia, Andrew J.

AU - Cescon, David

AU - Zhou, Lily

AU - Silvester, Jennifer

AU - Snow, Bryan

AU - Harris, Isaac S.

AU - Sasaki, Masato

AU - Li, Wanda Y.

AU - Itsumi, Momoe

AU - Yamamoto, Kazuo

AU - Ueda, Takeshi

AU - Dominguez-Brauer, Carmen

AU - Gorrini, Chiara

AU - Christine Chio, Iok In

AU - Haight, Jillian

AU - You-Ten, Annick

AU - McCracken, Susan

AU - Wakeham, Andrew

AU - Ghazarian, Danny

AU - Penn, Linda J Z

AU - Melino, Gerry

AU - Mak, Tak W.

PY - 2013/5/15

Y1 - 2013/5/15

N2 - 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.

AB - 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.

KW - c-Myc

KW - Huwe1

KW - Miz1

KW - Mule

KW - p21

KW - Ras

UR - http://www.scopus.com/inward/record.url?scp=84878154617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878154617&partnerID=8YFLogxK

U2 - 10.1101/gad.214577.113

DO - 10.1101/gad.214577.113

M3 - Article

C2 - 23699408

AN - SCOPUS:84878154617

VL - 27

SP - 1101

EP - 1114

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 10

ER -