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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 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 language | English |
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Journal | Nature Medicine |
Volume | 20 |
Issue number | 12 |
Pages (from-to) | 1401-1409 |
Number of pages | 9 |
ISSN | 1078-8956 |
DOIs | |
Publication status | Published - 01.12.2014 |
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
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Dive into the research topics of 'Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis'. Together they form a unique fingerprint.Projects
- 1 Finished
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Role of Cks1 for l-dependent and -indepentend cell cycle regulation, survival and quiescence in normal and leukemic hematopoiesis
von Bubnoff, N. (Project Staff) & Keller, U. (Principal Investigator (PI))
01.01.12 → 31.12.15
Project: DFG Projects › DFG Individual Projects