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.

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p53 deficient cells rely on ATM and ATR-mediated checkpoint signaling through the p38 MAPK/MK2pathway for survival after DNA damage

^{Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E18-580, Cambridge, MA, 02139 USA}

^{Division of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E18-580, Cambridge, MA, 02139 USA}

^{Address correspondence to: Michael B. Yaffe, Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E18-570, Cambridge, Massachusetts, USA, Ph: 617-452-2103, Fax: 617-452-4978, E-mail:}ude.tim@effaym

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Abstract

Summary

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.

Significance

Many anti-cancer agents induce DNA damage as part of their mechanism for tumor cytotoxicity. Here we show that DNA-damaging chemotherapeutic drugs directly activate the p38MAPK/MK2pathway downstream of ATM and ATR. In p53-proficient cells, signaling through this pathway is dispensable for survival after DNA damage. In marked contrast, however, activation of this pathway is essential for preventing chemotherapy-mediated cell death in p53-deficient cells. The finding that cells which lack functional p53 become dependent on recruiting a general stress kinase pathway to control the cell cycle rationalizes the therapeutic targeting of MK2as a new strategy to selectively kill p53-defective tumor cells with low dose chemotherapy.

Abstract

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