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

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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.We thank SY Kim and DH Lee for providing plasmids and JJ Hwang for providing renal cancer cell line lysates. We also thank KH Chun, IK Chung and J Song for their technical assistances, critical comments and helpful discussions. This research was supported by grants from the National Research Foundation of Korea (NRF; 2014M3C7A1064545 to KCC) funded by the Ministry of Science, ICT & Future Planning (MSIP), Republic of Korea, and from the Korea Healthcare Technology R&D Project (HI14C0093 to KCC) through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. This work was supported in part by NRF grants (2015R1A2A2A01003080 and 2007-0056092 to KCC)

Topics: CHRONIC KIDNEY-DISEASE, HEAT-SHOCK PROTEINS, TISSUE TRANSGLUTAMINASE, CELL CARCINOMA, BREAST-CANCER, PROTEASOMAL DEGRADATION, E3 LIGASE, PROGNOSTIC-SIGNIFICANCE, CROSS-LINKING, EXPRESSION
Publisher: NATURE PUBLISHING GROUP
Year: 2015
DOI identifier: 10.1038/onc.2015.439
OAI identifier: oai:repository.hanyang.ac.kr:20.500.11754/28804
Provided by: HANYANG Repository
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