p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage

Cancer Cell. 2007 Feb;11(2):175-89. doi: 10.1016/j.ccr.2006.11.024.

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

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

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Antineoplastic Agents / pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Cycle Proteins / metabolism*
  • Cell Division / drug effects
  • Cell Division / radiation effects
  • Cell Survival
  • Cells, Cultured
  • Cisplatin / pharmacology
  • DNA Damage / drug effects
  • DNA Damage / radiation effects
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • DNA-Binding Proteins / metabolism*
  • Doxorubicin / pharmacology
  • G2 Phase / drug effects
  • G2 Phase / radiation effects
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Mitosis / drug effects
  • Mitosis / radiation effects
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinases / genetics
  • Protein Kinases / physiology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • S Phase / drug effects
  • S Phase / radiation effects
  • Signal Transduction*
  • Staurosporine / analogs & derivatives
  • Staurosporine / pharmacology
  • Tumor Suppressor Protein p53 / physiology*
  • Tumor Suppressor Proteins / metabolism*
  • Ultraviolet Rays
  • cdc25 Phosphatases / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • 7-hydroxystaurosporine
  • Doxorubicin
  • Protein Kinases
  • Atr protein, mouse
  • MAP-kinase-activated kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • Protein Kinase C
  • p38 Mitogen-Activated Protein Kinases
  • CDC25A protein, human
  • CDC25B protein, human
  • Cdc25a protein, mouse
  • cdc25 Phosphatases
  • Staurosporine
  • Cisplatin