Conversion of cell-survival activity of Akt into apoptotic death of cancer cells by two mutations on the BIM BH3 domain
DC Field | Value | Language |
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dc.contributor.author | Kim, J-S | - |
dc.contributor.author | Ku, B | - |
dc.contributor.author | Woo, T-G | - |
dc.contributor.author | Oh, A-Y | - |
dc.contributor.author | Jung, Youn Sang | - |
dc.contributor.author | Soh, Y-M | - |
dc.contributor.author | Yeom, J-H | - |
dc.contributor.author | Lee, Kangseok | - |
dc.contributor.author | Park, B-J | - |
dc.contributor.author | Oh, B-H | - |
dc.contributor.author | Ha, N-C | - |
dc.date.available | 2019-03-08T17:00:31Z | - |
dc.date.issued | 2015-07 | - |
dc.identifier.issn | 2041-4889 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/9416 | - |
dc.description.abstract | Survival and proliferation of cancer cells are often associated with hyperactivity of the serine/threonine kinase, Akt. Herein, we show that prosurvival activity of Akt can be converted into prodeath activity by embedding an Akt recognition sequence in the apoptogenic BH3 domain of human BIM. The recognition sequence was created by introducing two mutations, I155R and E158S, into the core region of the BIM BH3 domain. Although a 21-mer BIM BH3 peptide containing these two mutations bound weakly to BCL-X-L and BCL-2, this peptide with phosphorylation of Ser158 bound to these proteins with a dissociation constant of <10 nM. The crystal structure of the phosphorylated peptide bound to BCL-X-L revealed that the phospho-Ser158 makes favorable interactions with two BCL-X-L residues, which cannot be formed with unphosphorylated Ser158. Remarkably, the designed peptide showed a cytotoxic effect on PTEN-null PC3 tumor cells whose Akt activity is aberrantly high. The cell-killing activity disappeared when the cellular Akt activity was lowered by ectopic PTEN expression. Thus, these results lay a foundation for developing a peptide or protein agent that is dormant in normal cells but is transformed into a potent apoptogenic molecule upon phosphorylation by hyperactivity of Akt in cancer cells. | - |
dc.language | 영어 | - |
dc.language.iso | ENG | - |
dc.publisher | NATURE PUBLISHING GROUP | - |
dc.title | Conversion of cell-survival activity of Akt into apoptotic death of cancer cells by two mutations on the BIM BH3 domain | - |
dc.type | Article | - |
dc.identifier.doi | 10.1038/cddis.2015.118 | - |
dc.identifier.bibliographicCitation | CELL DEATH & DISEASE, v.6 | - |
dc.description.isOpenAccess | Y | - |
dc.identifier.wosid | 000358788800004 | - |
dc.identifier.scopusid | 2-s2.0-84942941184 | - |
dc.citation.title | CELL DEATH & DISEASE | - |
dc.citation.volume | 6 | - |
dc.type.docType | Article | - |
dc.publisher.location | 영국 | - |
dc.subject.keywordPlus | MEMBRANE PERMEABILIZATION | - |
dc.subject.keywordPlus | MITOCHONDRIAL APOPTOSIS | - |
dc.subject.keywordPlus | CRYSTAL-STRUCTURE | - |
dc.subject.keywordPlus | PEPTIDE COMPLEX | - |
dc.subject.keywordPlus | IN-VIVO | - |
dc.subject.keywordPlus | X-RAY | - |
dc.subject.keywordPlus | BCL-2 | - |
dc.subject.keywordPlus | BAX | - |
dc.subject.keywordPlus | FAMILY | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.relation.journalResearchArea | Cell Biology | - |
dc.relation.journalWebOfScienceCategory | Cell Biology | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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