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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
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 1340-3443
e-ISSN 1861-0293
Quellenangaben Band: 20, Heft: 12, Seiten: 1401-1409 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Tokyo [u.a.]
Begutachtungsstatus Peer reviewed