p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage.
In response to DNA damage, eukaryotic cells activate ATM-Chk2 and/or ATR-Chk1 to arrest the cell cycle and initiate DNA repair. We show that, in the absence of p53, cells depend on a third cell-cycle checkpoint pathway involving p38MAPK/MK2 for cell-cycle arrest and survival after DNA damage. MK2 depletion in p53-deficient cells, but not in p53 wild-type cells, caused abrogation of the Cdc25A-mediated S phase checkpoint after cisplatin exposure and loss of the Cdc25B-mediated G2/M checkpoint following doxorubicin treatment, resulting in mitotic catastrophe and pronounced regression of murine tumors in vivo. We show that the Chk1 inhibitor UCN-01 also potently inhibits MK2, suggesting that its clinical efficacy results from the simultaneous disruption of two critical checkpoint pathways in p53-defective cells.
Reinhardt
H Christian
HC
Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E18-580, Cambridge, MA 02139, USA.
Aslanian
Aaron S
AS
Lees
Jacqueline A
JA
Yaffe
Michael B
MB
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000528:radiation effects; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014466:Ultraviolet Rays; D020687:cdc25 Phosphatases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002945:Cisplatin; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D047908:Intracellular Signaling Peptides and Proteins; D011493:Protein Kinase C; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019311:Staurosporine; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D020687:cdc25 Phosphatases; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C054852:7-hydroxystaurosporine; C576897:Atr protein, mouse; C576324:ATM protein, human; C576325:Atm protein, mouse; C517004:CDC25A protein, human; C517008:CDC25B protein, human; C517005:Cdc25a protein, mouse