Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15.
Genes Dev
; 27(10): 1101-14, 2013 May 15.
Article
em En
| MEDLINE
| ID: mdl-23699408
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.
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Assunto principal:
Proteínas Nucleares
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Regulação para Baixo
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Proteína Oncogênica p21(ras)
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Transformação Celular Neoplásica
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Proteínas Proto-Oncogênicas c-myc
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Ubiquitina-Proteína Ligases
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Proteínas Inibidoras de STAT Ativados
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Inibidor de Quinase Dependente de Ciclina p15
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Inibidor de Quinase Dependente de Ciclina p21
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article