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

Stem Cell Reports. 2015 Mar 10;4(3):374-89. doi: 10.1016/j.stemcr.2015.01.019. Epub 2015 Feb 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • CDC2 Protein Kinase / antagonists & inhibitors*
  • CDC2 Protein Kinase / genetics
  • Cell Differentiation
  • Cell Line
  • Cell Transformation, Neoplastic* / genetics
  • Cell Transformation, Neoplastic* / metabolism
  • 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 / metabolism*
  • Embryonic Stem Cells / pathology
  • Gene Expression Regulation
  • Gene Knockout Techniques
  • Humans
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA Interference
  • Signal Transduction / drug effects*
  • Teratoma / etiology*
  • Teratoma / pathology
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Cyclin A
  • Cyclin B1
  • Cyclin B2
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Octamer Transcription Factor-3
  • Pmaip1 protein, mouse
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • CDC2 Protein Kinase