Mutação em NRAS causa uma síndrome autoimune linfoproliferativa humana / NRAS mutation causes a human autoimmune lymphoproliferative syndrome

AUTOR(ES)

João Bosco de Oliveira Filho

DATA DE PUBLICAÇÃO

2008

RESUMO

The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4-, CD8- ab T cells. Mutations in ALPS typically affect Fas-mediated apoptosis, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair Fas-mediated apoptosis. The increase in active, GTP-bound NRAS augmented RAF/MEK/ERK signaling which markedly decreased the pro-apoptotic protein BIM and attenuated intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects

ASSUNTO(S)

apoptosis proteínas proto-oncogênicas p21 (ras) bim mitogen activated protein kinase kinases autoimunidade proto-oncogene proteins p21 (ras) autoimmunity quinases de proteína quinase ativadas por mitógeno apoptose bcl-2 -like protein 11

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