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Nat Med. 2014 Dec;20(12):1401-9. doi: 10.1038/nm.3740. Epub 2014 Nov 24.

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

Author information

1
Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
2
Institute of Pathology, Julius-Maximilians-University and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.
3
Department of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany.
4
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.
5
Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
6
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.
7
Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
8
Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
9
Biotechnology Centre of Oslo, Oslo, Norway.
10
Institute of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
11
Department of Medicine III, University Hospital Munchen, Munich, Germany.
12
Translational Oncology, Department of Medicine A, Universitätsklinikum Münster, Münster, Germany.
13
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.
14
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.

Abstract

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.

PMID:
25419709
DOI:
10.1038/nm.3740
[Indexed for MEDLINE]

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