PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
Baumann, U.* ; Fernández-Sáiz, V.* ; Rudelius, M.* ; Lemeer, S.* ; Rad, R.* ; Knorn, A.M.* ; Slawska, J.* ; Engel, K.* ; Jeremias, I. ; Li, Z.* ; Tomiatti, V.* ; Illert, A.L.* ; Targosz, B.S.* ; Braun, M.* ; Perner, S.* ; Leitges, M.* ; Klapper, W.* ; Dreyling, M.* ; Miething, C.* ; Lenz, G.* ; Rosenwald, A.* ; Peschel, C.* ; Keller, U.* ; Kuster, B.* ; Bassermann, F.*

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

J. Nat. Med. 20, 1401-1409 (2014)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Scopus
Cited By
Altmetric
28.054
4.752
33
41
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 1340-3443
e-ISSN 1861-0293
Journal Journal of natural medicines
Quellenangaben Volume: 20, Issue: 12, Pages: 1401-1409 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Tokyo [u.a.]
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Immune Response and Infection
PSP Element(s) G-501590-001
PubMed ID 25419709
DOI 10.1038/nm.3740
WOS ID WOS:000345817900015
Erfassungsdatum 2014-11-26
[➜Report correction]