CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation

Stem Cell Reports
Noelle E HuskeyAndrei Goga

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.

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Citations

Feb 2, 2016·Seminars in Cell & Developmental Biology·Tara TeSlaaMichael A Teitell
Dec 25, 2015·Wiley Interdisciplinary Reviews. Developmental Biology·Floriana Bulic-JakusNino Sincic
Nov 2, 2015·Current Opinion in Cell Biology·Michael S KaretaMarius Wernig
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Jun 21, 2016·Gene·Dan-Dan WangJin-Hai Tang
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Nov 24, 2017·Cell Adhesion & Migration·Adelaide Ij YoungSamantha R Oakes
Sep 5, 2019·Nature Cell Biology·Lijun LiuPiotr Sicinski
Sep 12, 2016·Cellular and Molecular Life Sciences : CMLS·Xuemei FuYang Xu
Mar 2, 2017·Cellular and Molecular Life Sciences : CMLS·Ho-Chang JeongHyuk-Jin Cha
Aug 30, 2019·BMC Molecular and Cell Biology·Guillermo A Videla-RichardsonMaría E Scassa
Feb 14, 2017·Stem Cells Translational Medicine·Aurelie BedelSandrine Dabernat
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Apr 3, 2020·Molecular Cell·Wojciech MichowskiPiotr Sicinski
Aug 3, 2021·International Journal of Biological Macromolecules·Pooja MittalIndrakant Kumar Singh

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Methods Mentioned

BETA
transfection
fluorescence-activated cell sorting
Protein Assay
Xenograft

Software Mentioned

FlowJo ( Tree Star )
FlowJo
GraphPad Prism

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