CHIP-mediated degradation of transglutaminase 2 negatively regulates tumor growth and angiogenesis in renal cancer
| Autor: | Chae-Ok Yun, Kwang Chul Chung, Jong Yun Lee, Boram Min, Ju Sang Kim, Young Deuk Choi, Je-Min Choi, Hakbae Lee, Hye-Suk Park, Sungnack Lee, Suk-Chul Bae, Yan Li, Y. G. Kwon |
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| Rok vydání: | 2015 |
| Předmět: |
Male
0301 basic medicine Proteasome Endopeptidase Complex Cancer Research Tissue transglutaminase Ubiquitin-Protein Ligases Immunoblotting Transplantation Heterologous Mice Nude medicine.disease_cause 03 medical and health sciences Downregulation and upregulation Ubiquitin GTP-Binding Proteins Cell Line Tumor Genetics medicine Animals Humans Protein Glutamine gamma Glutamyltransferase 2 Carcinoma Renal Cell Molecular Biology Kidney Transglutaminases Neovascularization Pathologic biology Ubiquitination Cancer medicine.disease Immunohistochemistry Kidney Neoplasms Ubiquitin ligase Cell biology Gene Expression Regulation Neoplastic Mice Inbred C57BL HEK293 Cells 030104 developmental biology medicine.anatomical_structure Proteolysis Cancer cell biology.protein Carcinogenesis Protein Binding |
| Zdroj: | Oncogene. 35:3718-3728 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2015.439 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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