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

被引：52

作者：

Baumann, Ursula ^{[1
]}

Fernandez-Saiz, Vanesa ^{[1
]}

Rudelius, Martina ^{[2
,3
]}

Lemeer, Simone ^{[4
]}

Rad, Roland ^{[5
,6
,7
]}

Knorn, Anna-Maria ^{[1
]}

Slawska, Jolanta ^{[8
]}

Engel, Katharina ^{[1
]}

Jeremias, Irmela ^{[9
,10
]}

Li, Zhoulei ^{[8
]}

Tomiatti, Viktoriya ^{[1
]}

Illert, Anna-Lena ^{[11
]}

Targosz, Bianca-Sabrina ^{[1
]}

Braun, Martin ^{[12
]}

Perner, Sven ^{[12
]}

Leitges, Michael ^{[13
]}

Klapper, Wolfram ^{[14
,15
]}

Dreyling, Martin ^{[16
]}

Miething, Cornelius ^{[11
]}

Lenz, Georg ^{[17
]}

Rosenwald, Andreas ^{[2
,3
]}

Peschel, Christian ^{[1
,6
,7
]}

Keller, Ulrich ^{[1
,6
,7
]}

Kuster, Bernhard ^{[4
,6
,7
,18
]}

Bassermann, Florian ^{[1
,6
,7
]}

机构：

[1] Tech Univ Munich, Klinikum Rechts Isar, Dept Med 3, D-80290 Munich, Germany

[2] Univ Wurzburg, Inst Pathol, Wurzburg, Germany

[3] Comprehens Canc Ctr Mainfranken, Wurzburg, Germany

[4] Tech Univ Munich, Dept Prote & Bioanalyt, Freising Weihenstephan, Germany

[5] Tech Univ Munich, Klinikum Rechts Isar, Dept Med 2, D-80290 Munich, Germany

[6] German Canc Consortium DKTK, Heidelberg, Germany

[7] German Canc Res Ctr, Heidelberg, Germany

[8] Tech Univ Munich, Klinikum Rechts Isar, Dept Nucl Med, D-80290 Munich, Germany

[9] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Dept Gene Vectors, Munich, Germany

[10] Univ Munich, Dept Pediat, Dr von Hauner Childrens Hosp, Munich, Germany

[11] Univ Med Ctr Freiburg, Dept Hematol Oncol, Freiburg, Germany

[12] Univ Hosp Bonn, Inst Pathol, Dept Prostate Canc Res, Bonn, Germany

[13] Biotechnol Ctr Oslo, Oslo, Norway

[14] Univ Klinikum Schleswig Holstein, Inst Pathol, Hematopathol Sect, Kiel, Germany

[15] Univ Klinikum Schleswig Holstein, Lymph Node Registry, Kiel, Germany

[16] Univ Hosp Munchen, Dept Med 3, Munich, Germany

[17] Univ Klinikum Munster, Dept Med A, Munster, Germany

[18] CIPSM, Freising Weihenstephan, Germany

来源：

NATURE MEDICINE | 2014年 / 20卷 / 12期

关键词：

MANTLE-CELL LYMPHOMA; PROTEIN-KINASE-C; COMPARATIVE GENOMIC HYBRIDIZATION; DNA-DAMAGE-RESPONSE; HOMOZYGOUS DELETIONS; GENE-EXPRESSION; B-CELLS; HAX-1; DELTA; MYC;

D O I：

10.1038/nm.3740

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 BX 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 C delta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondria! 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 E mu-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.

引用

页码：1401 / 1409

页数：9

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