IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

被引：106

作者：

Ammirante, Massimo ^{[1
,2
,3
]}

Rosati, Alessandra ^{[1
,4
]}

Arra, Claudio ^{[4
,5
]}

Basile, Anna ^{[1
,4
]}

Falco, Antonia ^{[1
,4
]}

Festa, Michela ^{[1
,4
]}

Pascale, Maria ^{[1
,4
]}

d'Avenia, Morena ^{[1
,4
]}

Marzullo, Liberato ^{[1
,4
]}

Belisario, Maria Antonietta ^{[1
]}

De Marco, Margot ^{[1
,4
]}

Barbieri, Antonio ^{[5
]}

Giudice, Aldo ^{[5
]}

Chiappetta, Gennaro ^{[6
]}

Vuttariello, Emilia ^{[6
]}

Monaco, Mario ^{[6
]}

Bonelli, Patrizia ^{[5
]}

Salvatore, Gaetano ^{[7
]}

Di Benedetto, Maria ^{[7
]}

Deshmane, Satish L. ^{[8
]}

Khalili, Kamel ^{[8
]}

Turco, Maria Caterina ^{[1
,4
]}

Leone, Arturo ^{[1
]}

机构：

[1] Univ Salerno, Dept Pharmaceut Sci DiFarma, I-84084 Fisciano, Italy

[2] Univ Calif San Diego, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Sch Med, Ctr Canc, La Jolla, CA 92093 USA

[4] BioUniverSA SRL, I-84084 Fisciano, Italy

[5] Natl Canc Inst, Tumor Inst Fond Pascale, Anim Facil, I-80131 Naples, Italy

[6] Natl Canc Inst, Tumor Inst Fond Pascale, Funct Genom Unit, I-80131 Naples, Italy

[7] Univ Naples Federico II, I-80131 Naples, Italy

[8] Temple Univ, Dept Neurosci, Ctr Neurovirol, Philadelphia, PA 19122 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 16期

关键词：

BAG3; IKK-gamma; apoptosis; NF-KAPPA-B; HEAT-SHOCK FACTOR-1; CANCER-CELLS; GENE-EXPRESSION; TRANSCRIPTION FACTORS; MOLECULAR CHAPERONES; INDUCED APOPTOSIS; TNF-ALPHA; ADHESION; ACTIVATION;

D O I：

10.1073/pnas.0907696107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-kappa B pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKK gamma, increasing availability of IKK gamma and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-kappa B activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.

引用

页码：7497 / 7502

页数：6

共 54 条

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NEMO trimerizes through its coiled-coil C-terminal domain [J].