GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb
Open accessAbstract
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.
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GSK3β inhibition promotes myeloid differentiation and apoptosis in leukemia cells.
“GSK3b inhibition promotes myeloid differentiation and apoptosis in leukemia cells (27)(28)(29)(30); however, mechanisms underlying GSK3b inhibition leading to myeloid differentiation are poorly understood.”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [29]
The Results section reports that GSK3β inhibitor treatment increased apoptosis in leukemia cell lines. The paper does not report that inhibition promotes myeloid differentiation; its Introduction mentions differentiation only in connection with c-Myb, not GSK3β inhibition. No page numbers are available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredGSK3b inhibition overcomes differentiation block and induces apoptosis in leukemia.
“Owing to its oncogenic role in leukemia, GSK3b inhibition was shown to overcome differentiation block and induce apoptosis (29).”
From FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 (2021) · cites this paper as [29]
The Results section reports that GSK3β inhibitors increased apoptosis in Jurkat and K562 leukemia cells. The paper does not report that inhibition overcame a differentiation block; its discussion focuses on apoptosis and reduced expression of survival factors. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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GSK-3 as a novel prognostic indicator in leukemia
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Self-citation
- Authors
- Zhou, F., Zhang, L., van Laar, T., van Dam, H., & ten Dijke, P.
- Affiliations
- Leiden University Medical Center (NL)
- Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands
- Venue
- Molecular Biology of the Cell
- Published
- 2011-09-15
- Volume
- 22
- Issue
- 18
- Pages
- 3533-3540
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC3172276
- OpenAlex
- W2101471927
- Cited by
- 55
- References
- 43
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 2 · 2017: 5 · 2016: 6 · 2015: 2 · 2014: 5 · 2013: 6 · 2012: 7
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- Molecular Biology of the Cell (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (918.66.066)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- GSK3β, MYB, leukemia, apoptosis, cell survival, ubiquitination, protein degradation, Bcl-2, survivin, LEF1, transcriptional regulation, kinase inhibition
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Survivin, Cell Line, Cell Survival, Gene Expression Regulation, Humans, Indoles, Leukemia, Maleimides, Protein Binding, Gene Expression, Apoptosis, Genes, Reporter, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-myb, Intercellular Signaling Peptides and Proteins, Glycogen Synthase Kinase 3, Cell Proliferation, Luciferases, Renilla, Inhibitor of Apoptosis Proteins, Lymphoid Enhancer-Binding Factor 1, Ubiquitination, Proteolysis, Axin Protein
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