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CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation.
- Source :
-
Stem cell reports [Stem Cell Reports] 2015 Mar 10; Vol. 4 (3), pp. 374-89. Date of Electronic Publication: 2015 Feb 26. - Publication Year :
- 2015
-
Abstract
- Embryonic stem cells (ESCs) have adopted an accelerated cell-cycle program with shortened gap phases and precocious expression of cell-cycle regulatory proteins, including cyclins and cyclin-dependent kinases (CDKs). We examined the effect of CDK inhibition on the pathways regulating proliferation and survival of ESCs. We found that inhibiting cyclin-dependent kinase 1 (CDK1) leads to activation of the DNA damage response, nuclear p53 stabilization, activation of a subset of p53 target genes including NOXA, and negative regulation of the anti-apoptotic protein MCL1 in human and mouse ESCs, but not differentiated cells. We demonstrate that MCL1 is highly expressed in ESCs and loss of MCL1 leads to ESC death. Finally, we show that clinically relevant CDK1 inhibitors prevent formation of ESC-derived tumors and induce necrosis in established ESC-derived tumors. Our data demonstrate that ES cells are uniquely sensitive to CDK1 inhibition via a p53/NOXA/MCL1 pathway.<br /> (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Apoptosis genetics
CDC2 Protein Kinase genetics
Cell Differentiation
Cell Line
Cyclin A genetics
Cyclin B1 genetics
Cyclin B2 genetics
DNA Damage drug effects
Drug Resistance drug effects
Drug Resistance genetics
Embryonic Stem Cells cytology
Embryonic Stem Cells drug effects
Embryonic Stem Cells pathology
Gene Expression Regulation
Gene Knockout Techniques
Humans
Mice
Myeloid Cell Leukemia Sequence 1 Protein genetics
Octamer Transcription Factor-3 genetics
Octamer Transcription Factor-3 metabolism
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-bcl-2 genetics
RNA Interference
Teratoma pathology
Tumor Suppressor Protein p53 genetics
CDC2 Protein Kinase antagonists & inhibitors
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic metabolism
Embryonic Stem Cells metabolism
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Proto-Oncogene Proteins c-bcl-2 metabolism
Signal Transduction drug effects
Teratoma etiology
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2213-6711
- Volume :
- 4
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Stem cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 25733019
- Full Text :
- https://doi.org/10.1016/j.stemcr.2015.01.019