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CHIP-mediated degradation of transglutaminase 2 negatively regulates tumor growth and angiogenesis in renal cancer

Authors
 B Min  ;  H Park  ;  S Lee  ;  Y Li  ;  J-M Choi  ;  J Y Lee  ;  J Kim  ;  Y D Choi  ;  Y-G Kwon  ;  H-W Lee  ;  S-C Bae  ;  C-O Yun  ;  K C Chung 
Citation
 Oncogene, Vol.35(28) : 3718-3728, 2016 
Journal Title
 Oncogene 
ISSN
 0950-9232 
Issue Date
2016
MeSH
Animals ; Carcinoma, Renal Cell/blood supply ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/metabolism* ; Cell Line, Tumor ; GTP-Binding Proteins/genetics ; GTP-Binding Proteins/metabolism* ; Gene Expression Regulation, Neoplastic ; HEK293 Cells ; Humans ; Immunoblotting ; Immunohistochemistry ; Kidney Neoplasms/blood supply ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism* ; Male ; Mice, Inbred C57BL ; Mice, Nude ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism* ; Neovascularization, Pathologic/pathology ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Proteolysis ; Transglutaminases/genetics ; Transglutaminases/metabolism* ; Transplantation, Heterologous ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism* ; Ubiquitination
Abstract
The multifunctional enzyme transglutaminase 2 (TG2) primarily catalyzes cross-linking reactions of proteins via (γ-glutamyl) lysine bonds. Several recent findings indicate that altered regulation of intracellular TG2 levels affects renal cancer. Elevated TG2 expression is observed in renal cancer. However, the molecular mechanism underlying TG2 degradation is not completely understood. Carboxyl-terminus of Hsp70-interacting protein (CHIP) functions as an ubiquitin E3 ligase. Previous studies reveal that CHIP deficiency mice displayed a reduced life span with accelerated aging in kidney tissues. Here we show that CHIP promotes polyubiquitination of TG2 and its subsequent proteasomal degradation. In addition, TG2 upregulation contributes to enhanced kidney tumorigenesis. Furthermore, CHIP-mediated TG2 downregulation is critical for the suppression of kidney tumor growth and angiogenesis. Notably, our findings are further supported by decreased CHIP expression in human renal cancer tissues and renal cancer cells. The present work reveals that CHIP-mediated TG2 ubiquitination and proteasomal degradation represent a novel regulatory mechanism that controls intracellular TG2 levels. Alterations in this pathway result in TG2 hyperexpression and consequently contribute to renal cancer.
Full Text
http://www.nature.com/onc/journal/v35/n28/full/onc2015439a.html
DOI
10.1038/onc.2015.439
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
최영득(Choi, Young Deuk) ORCID logo https://orcid.org/0000-0002-8545-5797
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/151636
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