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The transcription factor MZF1 differentially regulates murine Mtor promoter variants linked to tumor susceptibility.
Zhang, Shuling; Shi, Wei; Ramsay, Edward S; Bliskovsky, Valery; Eiden, Adrian Max; Connors, Daniel; Steinsaltz, Matthew; DuBois, Wendy; Mock, Beverly A.
Afiliação
  • Zhang S; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892.
  • Shi W; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, Maryland 20892.
  • Ramsay ES; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892.
  • Bliskovsky V; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892.
  • Eiden AM; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892.
  • Connors D; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892.
  • Steinsaltz M; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892.
  • DuBois W; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892.
  • Mock BA; Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland 20892 mockb@mail.nih.gov.
J Biol Chem ; 294(45): 16756-16764, 2019 11 08.
Article em En | MEDLINE | ID: mdl-31548308
ABSTRACT
Mechanistic target of rapamycin (MTOR) is a highly conserved serine/threonine kinase that critically regulates cell growth, proliferation, differentiation, and survival. Previously, we have implicated Mtor as a plasmacytoma-resistance locus, Pctr2, in mice. Here, we report that administration of the tumor-inducing agent pristane decreases Mtor gene expression to a greater extent in mesenteric lymph nodes of BALB/cAnPt mice than of DBA/2N mice. We identified six allelic variants in the Mtor promoter region in BALB/cAnPt and DBA/2N mice. To determine the effects of these variants on Mtor transcription, we constructed a series of luciferase reporters containing these promoter variants and transfected them into mouse plasmacytoma cells. We could attribute the differences in Mtor promoter activity between the two mouse strains to a C → T change at the -6 position relative to the transcriptional start site Tssr 40273; a T at this position in the BALB promoter creates a consensus binding site for the transcription factor MZF1 (myeloid zinc finger 1). Results from electrophoretic mobility shift assays and DNA pulldown assays with ChIP-PCR confirmed that MZF1 binds to the cis-element TGGGGA located in the -6/-1 Mtor promoter region. Of note, MZF1 significantly and differentially down-regulated Mtor promoter activity, with MZF1 overexpression reducing Mtor expression more strongly in BALB mice than in DBA mice. Moreover, MZF1 overexpression reduced Mtor expression in both fibroblasts and mouse plasmacytoma cells, and Mzf1 knockdown increased Mtor expression in BALB3T3 and NIH3T3 fibroblast cells. Our results provide evidence that MZF1 down-regulates Mtor expression in pristane-induced plasmacytomas in mice.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plasmocitoma / Regiões Promotoras Genéticas / Predisposição Genética para Doença / Fatores de Transcrição Kruppel-Like / Serina-Treonina Quinases TOR / Mutação Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Biol Chem Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Plasmocitoma / Regiões Promotoras Genéticas / Predisposição Genética para Doença / Fatores de Transcrição Kruppel-Like / Serina-Treonina Quinases TOR / Mutação Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: J Biol Chem Ano de publicação: 2019 Tipo de documento: Article