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A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration
Members of the Bcl-2 protein family are frequently deregulated in tumors as they critically control cell death induction in mammalian cells. Alterations of these proteins may cause resistance to chemotherapy-induced cell death and immune responses. By serendipity we cloned a variant of the anti-apop...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787154/ https://www.ncbi.nlm.nih.gov/pubmed/23872733 |
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author | Hagenbuchner, Judith Kiechl-Kohlendorfer, Ursula Obexer, Petra Ausserlechner, Michael J. |
author_facet | Hagenbuchner, Judith Kiechl-Kohlendorfer, Ursula Obexer, Petra Ausserlechner, Michael J. |
author_sort | Hagenbuchner, Judith |
collection | PubMed |
description | Members of the Bcl-2 protein family are frequently deregulated in tumors as they critically control cell death induction in mammalian cells. Alterations of these proteins may cause resistance to chemotherapy-induced cell death and immune responses. By serendipity we cloned a variant of the anti-apoptotic Bcl2-family member Myeloid cell leukemia-1 (Mcl1) from human neuroblastoma and leukemia cells. This Mcl1L variant lacks a 45 bp sequence that codes for 15 highly conserved amino acids ranging from Gly158 to Asp172. This region is part of the so called PEST-sequence of Mcl1L and contains two phosphorylation sites (Ser159 and Thr163) that regulate Mcl1L stability. A caspase 3/caspase 8 cleavage site at Asp157 which has been reported to be critical for death-receptor-induced apoptosis and for the conversion of Mcl1L into a pro-apoptotic protein is also missing in this novel variant. Importantly, Mcl1L(delGly158-Asp172) bound significantly more pro-apoptotic Bim compared to Mcl1L and showed increased anti-proliferative and anti-apoptotic activity compared to Mcl1L during death receptor-induced cell death. This suggests that this novel Mcl1L variant efficiently protects tumor cells against extrinsic death signalling and therefore may provide a survival advantage for highly aggressive tumors. |
format | Online Article Text |
id | pubmed-3787154 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-37871542013-10-01 A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration Hagenbuchner, Judith Kiechl-Kohlendorfer, Ursula Obexer, Petra Ausserlechner, Michael J. Oncotarget Research Paper Members of the Bcl-2 protein family are frequently deregulated in tumors as they critically control cell death induction in mammalian cells. Alterations of these proteins may cause resistance to chemotherapy-induced cell death and immune responses. By serendipity we cloned a variant of the anti-apoptotic Bcl2-family member Myeloid cell leukemia-1 (Mcl1) from human neuroblastoma and leukemia cells. This Mcl1L variant lacks a 45 bp sequence that codes for 15 highly conserved amino acids ranging from Gly158 to Asp172. This region is part of the so called PEST-sequence of Mcl1L and contains two phosphorylation sites (Ser159 and Thr163) that regulate Mcl1L stability. A caspase 3/caspase 8 cleavage site at Asp157 which has been reported to be critical for death-receptor-induced apoptosis and for the conversion of Mcl1L into a pro-apoptotic protein is also missing in this novel variant. Importantly, Mcl1L(delGly158-Asp172) bound significantly more pro-apoptotic Bim compared to Mcl1L and showed increased anti-proliferative and anti-apoptotic activity compared to Mcl1L during death receptor-induced cell death. This suggests that this novel Mcl1L variant efficiently protects tumor cells against extrinsic death signalling and therefore may provide a survival advantage for highly aggressive tumors. Impact Journals LLC 2013-07-15 /pmc/articles/PMC3787154/ /pubmed/23872733 Text en Copyright: © 2013 Hagenbuchner et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited |
spellingShingle | Research Paper Hagenbuchner, Judith Kiechl-Kohlendorfer, Ursula Obexer, Petra Ausserlechner, Michael J. A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration |
title | A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration |
title_full | A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration |
title_fullStr | A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration |
title_full_unstemmed | A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration |
title_short | A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration |
title_sort | novel mcl1 variant inhibits apoptosis via increased bim sequestration |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787154/ https://www.ncbi.nlm.nih.gov/pubmed/23872733 |
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