Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Antineoplastic Agents / pharmacology
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Ataxia Telangiectasia Mutated Proteins
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Bone Neoplasms / metabolism
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Bone Neoplasms / pathology
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Cell Cycle Proteins / metabolism*
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Cell Division / drug effects
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Cell Division / radiation effects
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Cell Survival
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Cells, Cultured
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Cisplatin / pharmacology
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DNA Damage / drug effects
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DNA Damage / radiation effects
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DNA Repair / drug effects
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DNA Repair / radiation effects
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DNA-Binding Proteins / metabolism*
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Doxorubicin / pharmacology
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G2 Phase / drug effects
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G2 Phase / radiation effects
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Humans
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Intracellular Signaling Peptides and Proteins
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Mice
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Mice, Knockout
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Mice, Nude
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Mitosis / drug effects
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Mitosis / radiation effects
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Neoplasms, Experimental / metabolism
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Neoplasms, Experimental / pathology
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Osteosarcoma / metabolism
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Osteosarcoma / pathology
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Phosphorylation / drug effects
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Phosphorylation / radiation effects
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Protein Kinase C / antagonists & inhibitors
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Protein Kinases / genetics
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Protein Kinases / physiology*
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Protein Serine-Threonine Kinases / metabolism*
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S Phase / drug effects
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S Phase / radiation effects
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Signal Transduction*
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Staurosporine / analogs & derivatives
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Staurosporine / pharmacology
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Tumor Suppressor Protein p53 / physiology*
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Tumor Suppressor Proteins / metabolism*
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Ultraviolet Rays
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cdc25 Phosphatases / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Antibiotics, Antineoplastic
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Antineoplastic Agents
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Cell Cycle Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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7-hydroxystaurosporine
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Doxorubicin
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Protein Kinases
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Atr protein, mouse
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MAP-kinase-activated kinase 2
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Protein Kinase C
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p38 Mitogen-Activated Protein Kinases
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CDC25A protein, human
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CDC25B protein, human
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Cdc25a protein, mouse
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cdc25 Phosphatases
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Staurosporine
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Cisplatin