Renal cell carcinoma escapes death by p53 depletion through transglutaminase 2-chaperoned autophagy
DC Field | Value | Language |
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dc.contributor.author | Kang, J. H. | - |
dc.contributor.author | Lee, J-S | - |
dc.contributor.author | Hong, D. | - |
dc.contributor.author | Lee, S-H | - |
dc.contributor.author | Kim, N. | - |
dc.contributor.author | Lee, W-K | - |
dc.contributor.author | Sung, T-W | - |
dc.contributor.author | Gong, Y-D | - |
dc.contributor.author | Kim, S-Y | - |
dc.date.accessioned | 2021-09-04T02:10:10Z | - |
dc.date.available | 2021-09-04T02:10:10Z | - |
dc.date.created | 2021-06-16 | - |
dc.date.issued | 2016-03 | - |
dc.identifier.issn | 2041-4889 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/89358 | - |
dc.description.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. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | NATURE PUBLISHING GROUP | - |
dc.subject | DNA-DAMAGE | - |
dc.subject | CANCER | - |
dc.subject | MDM2 | - |
dc.subject | DEGRADATION | - |
dc.subject | DOMAIN | - |
dc.subject | PHOSPHORYLATION | - |
dc.subject | INDUCTION | - |
dc.subject | APOPTOSIS | - |
dc.subject | TERMINUS | - |
dc.subject | PROTEINS | - |
dc.title | Renal cell carcinoma escapes death by p53 depletion through transglutaminase 2-chaperoned autophagy | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Lee, W-K | - |
dc.identifier.doi | 10.1038/cddis.2016.14 | - |
dc.identifier.scopusid | 2-s2.0-85013706317 | - |
dc.identifier.wosid | 000373489000008 | - |
dc.identifier.bibliographicCitation | CELL DEATH & DISEASE, v.7 | - |
dc.relation.isPartOf | CELL DEATH & DISEASE | - |
dc.citation.title | CELL DEATH & DISEASE | - |
dc.citation.volume | 7 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Cell Biology | - |
dc.relation.journalWebOfScienceCategory | Cell Biology | - |
dc.subject.keywordPlus | DNA-DAMAGE | - |
dc.subject.keywordPlus | CANCER | - |
dc.subject.keywordPlus | MDM2 | - |
dc.subject.keywordPlus | DEGRADATION | - |
dc.subject.keywordPlus | DOMAIN | - |
dc.subject.keywordPlus | PHOSPHORYLATION | - |
dc.subject.keywordPlus | INDUCTION | - |
dc.subject.keywordPlus | APOPTOSIS | - |
dc.subject.keywordPlus | TERMINUS | - |
dc.subject.keywordPlus | PROTEINS | - |
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