Cargando…
GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb
Glycogen synthase kinase 3β (GSK3β) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3β kinase activity has been reported to be critical for various types of cancer cells, but the mechanism has remained elusive. In this study we exami...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2011
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172276/ https://www.ncbi.nlm.nih.gov/pubmed/21795403 http://dx.doi.org/10.1091/mbc.E11-06-0483 |
_version_ | 1782211852834439168 |
---|---|
author | Zhou, Fangfang Zhang, Long van Laar, Theo van Dam, Hans ten Dijke, Peter |
author_facet | Zhou, Fangfang Zhang, Long van Laar, Theo van Dam, Hans ten Dijke, Peter |
author_sort | Zhou, Fangfang |
collection | PubMed |
description | Glycogen synthase kinase 3β (GSK3β) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3β kinase activity has been reported to be critical for various types of cancer cells, but the mechanism has remained elusive. In this study we examine the mechanism by which GSK3β regulates the survival of leukemia cells. We demonstrate that upon GSK3β kinase inhibition different types of leukemia cells show severe proliferation defects as a result of apoptosis. The transcription factor c-Myb is found to be the main target of GSK3β inhibition in cell survival. GSK3β inactivation reduces the expression of c-Myb by promoting its ubiquitination-mediated degradation, thereby inhibiting the expression of c-Myb–dependent antiapoptotic genes Bcl2 and survivin. Coimmunoprecipitation, reporter assays, chromatin immunoprecipitation, and knockdown studies show that c-Myb needs to interact and cooperate with transcription factor LEF-1 in the activation of Bcl2 and survivin and that both transcription factors are required for cell survival. These data reveal an as-yet-unknown mechanism by which GSK3β controls cell survival. |
format | Online Article Text |
id | pubmed-3172276 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-31722762011-11-30 GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb Zhou, Fangfang Zhang, Long van Laar, Theo van Dam, Hans ten Dijke, Peter Mol Biol Cell Articles Glycogen synthase kinase 3β (GSK3β) regulates diverse physiological processes, including metabolism, development, oncogenesis, and neuroprotection. GSK3β kinase activity has been reported to be critical for various types of cancer cells, but the mechanism has remained elusive. In this study we examine the mechanism by which GSK3β regulates the survival of leukemia cells. We demonstrate that upon GSK3β kinase inhibition different types of leukemia cells show severe proliferation defects as a result of apoptosis. The transcription factor c-Myb is found to be the main target of GSK3β inhibition in cell survival. GSK3β inactivation reduces the expression of c-Myb by promoting its ubiquitination-mediated degradation, thereby inhibiting the expression of c-Myb–dependent antiapoptotic genes Bcl2 and survivin. Coimmunoprecipitation, reporter assays, chromatin immunoprecipitation, and knockdown studies show that c-Myb needs to interact and cooperate with transcription factor LEF-1 in the activation of Bcl2 and survivin and that both transcription factors are required for cell survival. These data reveal an as-yet-unknown mechanism by which GSK3β controls cell survival. The American Society for Cell Biology 2011-09-15 /pmc/articles/PMC3172276/ /pubmed/21795403 http://dx.doi.org/10.1091/mbc.E11-06-0483 Text en © 2011 Zhou et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Zhou, Fangfang Zhang, Long van Laar, Theo van Dam, Hans ten Dijke, Peter GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb |
title | GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb |
title_full | GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb |
title_fullStr | GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb |
title_full_unstemmed | GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb |
title_short | GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb |
title_sort | gsk3β inactivation induces apoptosis of leukemia cells by repressing the function of c-myb |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172276/ https://www.ncbi.nlm.nih.gov/pubmed/21795403 http://dx.doi.org/10.1091/mbc.E11-06-0483 |
work_keys_str_mv | AT zhoufangfang gsk3binactivationinducesapoptosisofleukemiacellsbyrepressingthefunctionofcmyb AT zhanglong gsk3binactivationinducesapoptosisofleukemiacellsbyrepressingthefunctionofcmyb AT vanlaartheo gsk3binactivationinducesapoptosisofleukemiacellsbyrepressingthefunctionofcmyb AT vandamhans gsk3binactivationinducesapoptosisofleukemiacellsbyrepressingthefunctionofcmyb AT tendijkepeter gsk3binactivationinducesapoptosisofleukemiacellsbyrepressingthefunctionofcmyb |