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J Biol Chem ; 289(39): 26804-26816, 2014 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-25096573

RESUMO

Tumors are often greatly dependent on signaling cascades promoting cell growth or survival and may become hypersensitive to inactivation of key components within these signaling pathways. Ras and RAF mutations found in human cancer confer constitutive activity to these signaling molecules thereby converting them into an oncogenic state. RAF dimerization is required for normal Ras-dependent RAF activation and is required for the oncogenic potential of mutant RAFs. Here we describe a new mouse model for lung tumor development to investigate the role of B-RAF in oncogenic C-RAF-mediated adenoma initiation and growth. Conditional elimination of B-RAF in C-RAF BxB-expressing embryonic alveolar epithelial type II cells did not block adenoma formation. However, loss of B-RAF led to significantly reduced tumor growth. The diminished tumor growth upon B-RAF inactivation was due to reduced cell proliferation in absence of senescence and increased apoptosis. Furthermore, B-RAF elimination inhibited C-RAF BxB-mediated activation of the mitogenic cascade. In line with these data, mutation of Ser-621 in C-RAF BxB abrogated in vitro the dimerization with B-RAF and blocked the ability to activate the MAPK cascade. Taken together these data indicate that B-RAF is an important factor in oncogenic C-RAF-mediated tumorigenesis.


Assuntos
Adenoma/enzimologia , Transformação Celular Neoplásica/metabolismo , Células Epiteliais/enzimologia , Neoplasias Pulmonares/enzimologia , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Alvéolos Pulmonares/enzimologia , Mucosa Respiratória/enzimologia , Adenoma/genética , Adenoma/patologia , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Epiteliais/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Alvéolos Pulmonares/patologia , Mucosa Respiratória/patologia
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