Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis.

Autor:	Baumann U; Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany., Fernández-Sáiz V; Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany., Rudelius M; Institute of Pathology, Julius-Maximilians-University and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany., Lemeer S; Department of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany., Rad R; 1] Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Knorn AM; Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany., Slawska J; Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany., Engel K; Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany., Jeremias I; 1] Department of Gene Vectors, Helmholtz Center Munich-German Research Center for Environmental Health, Munich, Germany. [2] Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany., Li Z; Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany., Tomiatti V; Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany., Illert AL; Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany., Targosz BS; Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany., Braun M; Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany., Perner S; Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany., Leitges M; Biotechnology Centre of Oslo, Oslo, Norway., Klapper W; Institute of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Kiel, Germany., Dreyling M; Department of Medicine III, University Hospital Munchen, Munich, Germany., Miething C; Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany., Lenz G; Translational Oncology, Department of Medicine A, Universitätsklinikum Münster, Münster, Germany., Rosenwald A; Institute of Pathology, Julius-Maximilians-University and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany., Peschel C; 1] Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Keller U; 1] Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Kuster B; 1] Department of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany. [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. [3] Center for Integrated Protein Science Munich (CIPSM), Freising, Germany., Bassermann F; 1] Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Nature medicine [Nat Med] 2014 Dec; Vol. 20 (12), pp. 1401-9. Date of Electronic Publication: 2014 Nov 24.
DOI:	10.1038/nm.3740
Abstrakt:	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:	MEDLINE
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