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Nat Med ; 20(12): 1401-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25419709

RESUMO

We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase Cδ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in Eµ-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/genética , Proteínas F-Box/genética , Linfoma de Células B/genética , Linfoma de Célula do Manto/genética , Proteínas do Tecido Nervoso/genética , Proteína Quinase C-delta/genética , Proto-Oncogenes/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Animais , Humanos , Linfoma de Células B/metabolismo , Linfoma de Célula do Manto/metabolismo , Camundongos , Proto-Oncogene Mas , Transdução de Sinais/genética
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