Disruption of the PRKCD–FBXO25–HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis
| Autor: | Bianca-Sabrina Targosz, Simone Lemeer, Christian Peschel, Roland Rad, Bernhard Kuster, Michael Leitges, A L Illert, Katharina Engel, Georg Lenz, Martin Braun, Irmela Jeremias, Martina Rudelius, Viktoriya Tomiatti, Cornelius Miething, Martin Dreyling, Jolanta Slawska, Ursula Baumann, Ulrich Keller, Wolfram Klapper, Sven Perner, Anna-Maria Knorn, Andreas Rosenwald, Florian Bassermann, Vanesa Fernández-Sáiz, Zhoulei Li |
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| Rok vydání: | 2014 |
| Předmět: |
Lymphoma
B-Cell SKP Cullin F-Box Protein Ligases biology Chemistry Kinase F-Box Proteins Ubiquitin-Protein Ligase Complexes Apoptosis Nerve Tissue Proteins Lymphoma Mantle-Cell General Medicine Proto-Oncogene Mas General Biochemistry Genetics and Molecular Biology Ubiquitin ligase Cell biology Mice Protein Kinase C-delta PRKCD Proto-Oncogenes biology.protein Animals Humans Adaptor Proteins Signal Transducing Signal Transduction |
| Zdroj: | Nature Medicine. 20:1401-1409 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.3740 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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