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Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest
1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
The p38 group of kinases belongs to the mitogen-activated protein (MAP) kinase superfamily with structural and functional characteristics distinguishable from those of the ERK, JNK (SAPK), and BMK (ERK5) kinases. Although there is a high degree of similarity among members of the p38 group in terms of structure and activation, each member appears to have a unique function. Here we show that activation of p38gamma (also known as ERK6 or SAPK3), but not the other p38 isoforms, is required for gamma-irradiation-induced G(2) arrest. Activation of the MKK6-p38gamma cascade is sufficient to induce G(2) arrest in cells, and expression of dominant negative alleles of MKK6 or p38gamma allows cells to escape the DNA damage-induce G(2) delay. Activation of p38gamma is dependent on ATM and leads to activation of Cds1 (also known as Chk2). These data suggest a model in which activation of ATM by gamma irradiation leads to the activation of MKK6, p38gamma, and Cds1 and that activation of both MKK6 and p38gamma is essential for the proper regulation of the G(2) checkpoint in mammalian cells.
Insights
The p38gamma kinase is essential for the gamma-irradiation-induced G(2) cell cycle arrest. Its activation, along with MKK6, is crucial for DNA damage response and the G(2) checkpoint in mammalian cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The p38 group of kinases is part of the mitogen-activated protein (MAP) kinase superfamily.
- While structurally similar, p38 isoforms possess distinct functions.
- Understanding p38 isoform roles in cellular processes like DNA damage response is critical.
Purpose of the Study:
- To investigate the specific role of p38 isoforms in gamma-irradiation-induced G(2) arrest.
- To elucidate the signaling pathway involved in DNA damage-induced G(2) checkpoint activation.
Main Methods:
- Utilized gamma irradiation to induce DNA damage.
- Investigated the activation of p38 isoforms, MKK6, ATM, and Cds1 (Chk2).
- Employed dominant-negative alleles to assess the necessity of MKK6 and p38gamma in G(2) arrest.
Main Results:
- p38gamma activation, but not other p38 isoforms, is required for gamma-irradiation-induced G(2) arrest.
- The MKK6-p38gamma cascade activation is sufficient to induce G(2) arrest.
- p38gamma activation is ATM-dependent and leads to Cds1 (Chk2) activation.
- Inhibition of MKK6 or p38gamma abrogates the DNA damage-induced G(2) delay.
Conclusions:
- A signaling cascade involving ATM, MKK6, p38gamma, and Cds1 (Chk2) is essential for the G(2) checkpoint regulation following gamma irradiation.
- p38gamma plays a unique and critical role in mediating the G(2) arrest in response to DNA damage.