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Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and -independent mechanisms
P Pandey1, J Raingeaud, M Kaneki
1Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
The p38 mitogen-activated protein (MAP) kinase defines a subgroup of the mammalian MAP kinases that are induced in response to lipopolysaccharide, hyperosmolarity, and interleukin 1. p38 MAP kinase appears to play a role in regulating inflammatory responses, including cytokine secretion and apoptosis. Here we show that diverse classes of DNA-damaging agents such as cisplatinum, 1-beta-D-arabinofuranosylcytosine, UV light, ionizing radiation, and methyl methanesulfonate activate p38 MAP kinase. We also demonstrate that cells deficient in c-Abl fail to activate p38 MAP kinase after treatment with cisplatinum and 1-beta-D-arabinofuranosylcytosine but not after exposure to UV and methyl methanesulfonate. Reconstitution of c-Abl in the Abl-/- cells restores that response. Similar results were obtained for induction of the Jun-NH2-kinase/stress-activated protein kinase. These findings indicate that p38 MAP and Jun-NH2-kinase/stress-activated protein kinases are differentially regulated in response to different classes of DNA-damaging agents.
Insights
DNA-damaging agents activate p38 mitogen-activated protein (MAP) kinase and Jun-NH2-kinase. The c-Abl protein is crucial for activating these kinases in response to certain DNA-damaging agents, but not others.
Area of Science:
- Cellular signaling pathways
- DNA damage response
- Kinase regulation
Background:
- p38 mitogen-activated protein (MAP) kinase is a key regulator of inflammatory responses, including cytokine secretion and apoptosis.
- MAP kinases are activated by various cellular stresses, including lipopolysaccharide, hyperosmolarity, and interleukin 1.
Purpose of the Study:
- To investigate the activation of p38 MAP kinase by diverse DNA-damaging agents.
- To determine the role of c-Abl in the activation of p38 MAP kinase and Jun-NH2-kinase/stress-activated protein kinase in response to DNA damage.
Main Methods:
- Treatment of cells with various DNA-damaging agents: cisplatinum, 1-beta-D-arabinofuranosylcytosine, UV light, ionizing radiation, and methyl methanesulfonate.
- Analysis of p38 MAP kinase and Jun-NH2-kinase/stress-activated protein kinase activation in wild-type and c-Abl deficient cells.
- Reconstitution of c-Abl in Abl-/- cells to assess its role in kinase activation.
Main Results:
- Diverse classes of DNA-damaging agents activate p38 MAP kinase.
- Cells deficient in c-Abl fail to activate p38 MAP kinase in response to cisplatinum and 1-beta-D-arabinofuranosylcytosine, but not UV light or methyl methanesulfonate.
- Reconstitution of c-Abl restores the activation response.
- Similar differential regulation was observed for Jun-NH2-kinase/stress-activated protein kinase induction.
Conclusions:
- p38 MAP kinase and Jun-NH2-kinase/stress-activated protein kinases are differentially regulated by distinct classes of DNA-damaging agents.
- The c-Abl protein plays a critical, but agent-specific, role in the activation of these stress-activated protein kinases following DNA damage.