CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation.
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.
Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Noelle E
NE
Huskey
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Tingxia
T
Guo
Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Kimberley J
KJ
Evason
Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Olga
O
Momcilovic
Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
David
D
Pardo
Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Katelyn J
KJ
Creasman
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
Robert L
RL
Judson
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA.
Robert
R
Blelloch
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Scott A
SA
Oakes
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Matthias
M
Hebrok
Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: andrei.goga@ucsf.edu.
Andrei
A
Goga
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D019925:Cyclin A / Q000235:genetics; D056744:Cyclin B1 / Q000235:genetics; D056765:Cyclin B2 / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects*; D013724:Teratoma / Q000209:etiology* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D019925:Cyclin A; D056744:Cyclin B1; D056765:Cyclin B2; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050814:Octamer Transcription Factor-3; C408009:Pmaip1 protein, mouse; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase