title: Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis.
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.
authors.affiliation: Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Baumann
authors.affiliation: Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Fernández-Sáiz
authors.affiliation: Institute of Pathology, Julius-Maximilians-University and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Rudelius
authors.affiliation: Department of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Lemeer
authors.affiliation: 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.
authors.forename: Roland
authors.initials: R
authors.lastname: Rad
authors.affiliation: Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Knorn
authors.affiliation: Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Slawska
authors.affiliation: Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Engel
authors.affiliation: 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.
authors.forename: Irmela
authors.initials: I
authors.lastname: Jeremias
authors.affiliation: Department of Nuclear Medicine, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Zhoulei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Tomiatti
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Illert
authors.affiliation: Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Bianca-Sabrina
authors.initials: BS
authors.lastname: Targosz
authors.affiliation: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Braun
authors.affiliation: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.affiliation: Biotechnology Centre of Oslo, Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: Institute of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Department of Medicine III, University Hospital Munchen, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Miething
authors.affiliation: Translational Oncology, Department of Medicine A, Universitätsklinikum Münster, Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Institute of Pathology, Julius-Maximilians-University and Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.affiliation: 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.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
authors.affiliation: 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.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kuster
authors.affiliation: 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Bassermann
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051745:Protein Kinase C-delta / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D044783:F-Box Proteins; C510759:FBXO25 protein, human; C104759:HAX1 protein, human; C000715470:MAS1 protein, human; D009419:Nerve Tissue Proteins; D000090063:Proto-Oncogene Mas; D043743:Ubiquitin-Protein Ligase Complexes; D044843:SKP Cullin F-Box Protein Ligases; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta