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

Ursula Baumann, Vanesa Fernández-Saíz, Martina Rudelius, Simone Lemeer, Roland Rad, Anna Maria Knorn, Jolanta Slawska, Katharina Engel, Irmela Jeremias, Zhoulei Li, Viktoriya Tomiatti, Anna Lena Illert, Bianca Sabrina Targosz, Martin Braun, Sven Perner, Michael Leitges, Wolfram Klapper, Martin Dreyling, Cornelius Miething, Georg LenzAndreas Rosenwald, Christian Peschel, Ulrich Keller, Bernhard Kuster, Florian Bassermann*

*Corresponding author for this work
25 Citations (Scopus)


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 CÎ (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 EÎ 1/4-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.

Original languageEnglish
JournalNature Medicine
Issue number12
Pages (from-to)1401-1409
Number of pages9
Publication statusPublished - 01.12.2014

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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