BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis in diffuse large B-cell lymphoma

被引：58

作者：

Camicia, Rosalba ^{[1
]}

Bachmann, Samia B. ^{[1
]}

Winkler, Hans C. ^{[1
]}

Beer, Marc ^{[2
]}

Tinguely, Marianne ^{[2
]}

Haralambieva, Eugenia ^{[2
]}

Hassa, Paul O. ^{[1
]}

机构：

[1] Univ Zurich, Inst Vet Biochem & Mol Biol, CH-8057 Zurich, Switzerland

[2] Univ Zurich Hosp, Inst Surg Pathol, CH-8057 Zurich, Switzerland

来源：

JOURNAL OF CELL SCIENCE | 2013年 / 126卷 / 09期

基金：

瑞士国家科学基金会;

关键词：

BAL1/ARTD9; Diffuse large B-cell lymphoma; Macrodomains; IFN gamma-STAT1-signaling; Survival; ADP-ribosylation; IRF1; p53; NF-KAPPA-B; POLY(ADP-RIBOSE) POLYMERASE-ACTIVITY; DEPENDENT GENE-EXPRESSION; TRANSCRIPTIONAL ACTIVATION; BREAST-CANCER; FAMILY; STAT1; RESISTANCE; PATHWAY; P53;

D O I：

10.1242/jcs.118174

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The B-aggressive lymphoma-1 protein and ADP-ribosyltransferase BAL1/ARTD9 has been recently identified as a risk-related gene product in aggressive diffuse large B-cell lymphoma (DLBCL). BAL1 is constitutively expressed in a subset of high-risk DLBCLs with an active host inflammatory response and has been suggested to be associated with interferon-related gene expression. Here we identify BAL1 as a novel oncogenic survival factor in DLBCL and show that constitutive overexpression of BAL1 in DLBCL tightly associates with intrinsic interferon-gamma (IFN gamma) signaling and constitutive activity of signal transducer and activator of transcription (STAT)-1. Remarkably, BAL1 stimulates the phosphorylation of both STAT1 isoforms, STAT1 alpha and STAT1 beta, on Y701 and thereby promotes the nuclear accumulation of the antagonistically acting and transcriptionally repressive isoform STAT1 beta. Moreover, BAL1 physically interacts with both STAT1 alpha and STAT1 beta through its macrodomains in an ADP-ribosylation-dependent manner. BAL1 directly inhibits, together with STAT1 beta, the expression of tumor suppressor and interferon response factor (IRF)-1. Conversely, BAL1 enhances the expression of the proto-oncogenes IRF2 and B-cell CLL/lymphoma (BCL)-6 in DLBCL. Our results show for the first time that BAL1 represses the anti-proliferative and pro-apoptotic IFN gamma-STAT1-IRF1-p53 axis and mediates proliferation, survival and chemo-resistance in DLBCL. As a consequence constitutive IFN gamma-STAT1 signaling does not lead to apoptosis but rather to chemo-resistance in DLBCL overexpressing BAL1. Our results suggest that BAL1 may induce an switch in STAT1 from a tumor suppressor to an oncogene in high-risk DLBCL.

引用

页码：1969 / 1980

页数：12

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