Your browser doesn't support javascript.
loading
BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4.
Morita, K; Masamoto, Y; Kataoka, K; Koya, J; Kagoya, Y; Yashiroda, H; Sato, T; Murata, S; Kurokawa, M.
Afiliação
  • Morita K; Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Masamoto Y; Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Kataoka K; Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Koya J; Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Kagoya Y; Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Yashiroda H; Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
  • Sato T; Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • Murata S; Department of Transfusion Medicine, The University of Tokyo Hospital, Tokyo, Japan.
  • Kurokawa M; Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Leukemia ; 29(11): 2248-56, 2015 Nov.
Article em En | MEDLINE | ID: mdl-26050649
Although high brain and acute leukemia, cytoplasmic (BAALC) expression is a well-characterized poor prognostic factor in acute myeloid leukemia (AML), neither the exact mechanisms by which BAALC drives leukemogenesis and drug resistance nor therapeutic approaches against BAALC-high AML have been properly elucidated. In this study, we found that BAALC induced cell-cycle progression of leukemia cells by sustaining extracellular signal-regulated kinase (ERK) activity through an interaction with a scaffold protein MEK kinase-1 (MEKK1), which inhibits the interaction between ERK and MAP kinase phosphatase 3 (MKP3/DUSP6). BAALC conferred chemoresistance in AML cells by upregulating ATP-binding cassette proteins in an ERK-dependent manner, which can be therapeutically targeted by MEK inhibitor. We also demonstrated that BAALC blocks ERK-mediated monocytic differentiation of AML cells by trapping Krüppel-like factor 4 (KLF4) in the cytoplasm and inhibiting its function in the nucleus. Consequently, MEK inhibition therapy synergizes with KLF4 induction and is highly effective against BAALC-high AML cells both in vitro and in vivo. Our data provide a molecular basis for the role of BAALC in regulating proliferation and differentiation of AML cells and highlight the unique dual function of BAALC as an attractive therapeutic target against BAALC-high AML.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Sistema de Sinalização das MAP Quinases / MAP Quinase Quinase Quinase 1 / MAP Quinases Reguladas por Sinal Extracelular / Fatores de Transcrição Kruppel-Like / Proteínas de Neoplasias Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leucemia Mieloide Aguda / Sistema de Sinalização das MAP Quinases / MAP Quinase Quinase Quinase 1 / MAP Quinases Reguladas por Sinal Extracelular / Fatores de Transcrição Kruppel-Like / Proteínas de Neoplasias Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2015 Tipo de documento: Article