Renal cell carcinoma escapes death by p53 depletion through transglutaminase 2-chaperoned autophagy
- Authors
- Kang, J. H.; Lee, J-S; Hong, D.; Lee, S-H; Kim, N.; Lee, W-K; Sung, T-W; Gong, Y-D; Kim, S-Y
- Issue Date
- 3월-2016
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- CELL DEATH & DISEASE, v.7
- Indexed
- SCIE
SCOPUS
- Journal Title
- CELL DEATH & DISEASE
- Volume
- 7
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/89358
- DOI
- 10.1038/cddis.2016.14
- ISSN
- 2041-4889
- Abstract
- In renal cell carcinoma, transglutaminase 2 (TGase 2) crosslinks p53 in autophagosomes, resulting in p53 depletion and the tumor's evasion of apoptosis. Inhibition of TGase 2 stabilizes p53 and induces tumor cells to enter apoptosis. This study explored the mechanism of TGase 2-dependent p53 degradation. We found that TGase 2 competes with human double minute 2 homolog (HDM2) for binding to p53; promotes autophagy-dependent p53 degradation in renal cell carcinoma (RCC) cell lines under starvation; and binds to p53 and p62 simultaneously without ubiquitin-dependent recognition of p62. The bound complex does not have crosslinking activity. A binding assay using a series of deletion mutants of p62, p53 and TGase 2 revealed that the PB1 (Phox and Bem1p-1) domain of p62 (residues 85-110) directly interacts with the beta-barrel domains of TGase 2 (residues 592-687), whereas the HDM2-binding domain (transactivation domain, residues 15-26) of p53 interacts with the N terminus of TGase 2 (residues 1-139). In addition to the increase in p53 stability due to TGase 2 inhibition, the administration of a DNA-damaging anti-cancer drug such as doxorubicin-induced apoptosis in RCC cell lines and synergistically reduced tumor volume in a xenograft model. Combination therapy with a TGase 2 inhibitor and a DNA-damaging agent may represent an effective therapeutic approach for treating RCC.
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