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

TitleMule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15
Authors
KeywordsMule
Miz1
Ras
c-Myc
Huwe1
p21
Issue Date2013
Citation
Genes and Development, 2013, v. 27, n. 10, p. 1101-1114 How to Cite?
AbstractTumorigenesis 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. © 2013 by Cold Spring Harbor Laboratory Press.
Persistent Identifierhttp://hdl.handle.net/10722/292750
ISSN
2023 Impact Factor: 7.5
2023 SCImago Journal Rankings: 5.015
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorInoue, Satoshi-
dc.contributor.authorHao, Zhenyue-
dc.contributor.authorElia, Andrew J.-
dc.contributor.authorCescon, David-
dc.contributor.authorZhou, Lily-
dc.contributor.authorSilvester, Jennifer-
dc.contributor.authorSnow, Bryan-
dc.contributor.authorHarris, Isaac S.-
dc.contributor.authorSasaki, Masato-
dc.contributor.authorLi, Wanda Y.-
dc.contributor.authorItsumi, Momoe-
dc.contributor.authorYamamoto, Kazuo-
dc.contributor.authorUeda, Takeshi-
dc.contributor.authorDominguez-Brauer, Carmen-
dc.contributor.authorGorrini, Chiara-
dc.contributor.authorChristine Chio, Iok In-
dc.contributor.authorHaight, Jillian-
dc.contributor.authorYou-Ten, Annick-
dc.contributor.authorMcCracken, Susan-
dc.contributor.authorWakeham, Andrew-
dc.contributor.authorGhazarian, Danny-
dc.contributor.authorPenn, Linda J.Z.-
dc.contributor.authorMelino, Gerry-
dc.contributor.authorMak, Tak W.-
dc.date.accessioned2020-11-17T14:57:08Z-
dc.date.available2020-11-17T14:57:08Z-
dc.date.issued2013-
dc.identifier.citationGenes and Development, 2013, v. 27, n. 10, p. 1101-1114-
dc.identifier.issn0890-9369-
dc.identifier.urihttp://hdl.handle.net/10722/292750-
dc.description.abstractTumorigenesis 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. © 2013 by Cold Spring Harbor Laboratory Press.-
dc.languageeng-
dc.relation.ispartofGenes and Development-
dc.subjectMule-
dc.subjectMiz1-
dc.subjectRas-
dc.subjectc-Myc-
dc.subjectHuwe1-
dc.subjectp21-
dc.titleMule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1101/gad.214577.113-
dc.identifier.pmid23699408-
dc.identifier.pmcidPMC3672645-
dc.identifier.scopuseid_2-s2.0-84878154617-
dc.identifier.volume27-
dc.identifier.issue10-
dc.identifier.spage1101-
dc.identifier.epage1114-
dc.identifier.eissn1549-5477-
dc.identifier.isiWOS:000319393800004-
dc.identifier.issnl0890-9369-

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