Abstract
p38 MAPK is mainly activated by stress stimuli and mediates signals that regulate various cellular responses, including cell-cycle progression and apoptosis, depending on cell types and stimuli. Here we examine the role of p38 in regulation of apoptosis and cell cycle checkpoint in Daudi B-cell lymphoma cells treated with the topoisomerase II inhibitor etoposide. Etoposide activated p38, inhibited the G2/M transition with the persistent inhibitory phosphorylation of Cdc2 on Tyr15, and caused apoptosis of Daudi cells. Inducible expression of a dominant negative p38α mutant in Daudi cells reduced the inhibition of Cdc2 as well as G2/M arrest and augmented apoptosis induced by etoposide. SB203580, a specific inhibitor of p38α and p38β, similarly reduced the inhibitory phosphorylation of Cdc2 as well as G2/M arrest and augmented apoptosis of Daudi cells treated with etoposide. These results suggest that p38 plays a role in G2/M checkpoint activation through induction of the persistent inhibitory phosphorylation of Cdc2 and, thereby, inhibits apoptosis of Daudi cells treated with etoposide. The present study, thus, raises the possibility that p38 may represent a new target for sensitization of lymphoma cells to DNA-damaging chemotherapeutic agents.
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Nyberg KA, Michelson RJ, Putnam CW, Weinert TA. Toward maintaining the genome: DNA damage and replication checkpoints. Annu Rev Genet 2002; 36: 617–656.
Sancar A, Lindsey-Boltz LA, Unsal-Kaccmaz K, Linn S. Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints. Annu Rev Biochem 2004; 73: 39–85.
Bartek J, Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 2003; 3: 421–429.
Zhou BB, Bartek J. Targeting the checkpoint kinases: Chemosensitization versus chemoprotection. Nat Rev Cancer 2004; 4: 216–225.
Nebreda AR, Porras A. p38 MAP kinases: Beyond the stress response. Trends Biochem Sci 2000; 25: 257–260.
Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 2001; 81: 807–869.
Kishi H, Nakagawa K, Matsumoto M, et al. Osmotic shock induces G1 arrest through p53 phosphorylation at Ser33 by activated p38MAPK without phosphorylation at Ser15 and Ser20. J Biol Chem 2001; 276: 39115–39122.
Bulavin DV, Saito S, Hollander MC, et al. Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation. Embo J 1999; 18: 6845–6854.
Wang X, McGowan CH, Zhao M, et al. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol 2000; 20: 4543–4552.
Bulavin DV, Higashimoto Y, Popoff IJ, Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 2001; 411: 102–107.
Hirose Y, Katayama M, Stokoe D, Haas-Kogan DA, Berger MS, Pieper RO. The p38 mitogen-activated protein kinase pathway links the DNA mismatch repair system to the G2 checkpoint and to resistance to chemotherapeutic DNA-methylating agents. Mol Cell Biol 2003; 23: 8306–8315.
Jin ZH, Kurosu T, Yamaguchi M, Arai A, Miura O. Hematopoietic cytokines enhance Chk1-dependent G2/M checkpoint activation by etoposide through the Akt/GSK3 pathway to inhibit apoptosis. Oncogene 2005; in press.
Engelman JA, Lisanti MP, Scherer PE. Specific inhibitors of p38 mitogen-activated protein kinase block 3T3-L1 adipogenesis. J Biol Chem 1998; 273: 32111–32120.
Kurosu T, Fukuda T, Miki T, Miura O. BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells. Oncogene 2003; 22: 4459–4468.
Sramkoski RM, Wormsley SW, Bolton WE, Crumpler DC, Jacobberger JW. Simultaneous detection of cyclin B1, p105, and DNA content provides complete cell cycle phase fraction analysis of cells that endoreduplicate. Cytometry 1999; 35: 274–283.
Mikhailov A, Shinohara M, Rieder CL. Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway. J Cell Biol 2004; 166: 517–526.
Lee JC, Kassis S, Kumar S, Badger A, Adams JL. p38 mitogen-activated protein kinase inhibitors-mechanisms and therapeutic potentials. Pharmacol Ther 1999; 82: 389–397.
Bulavin DV, Amundson SA, Fornace AJ. p38 and Chk1 kinases: Different conductors for the G(2)/M checkpoint symphony. Curr Opin Genet Dev 2002; 12: 92–97.
Hirose Y, Katayama M, Berger MS, Pieper RO. Cooperative function of Chk1 and p38 pathways in activating G2 arrest following exposure to temozolomide. J Neurosurg 2004; 100: 1060–1065.
Zechner D, Craig R, Hanford DS, McDonough PM, Sabbadini RA, Glembotski CC. MKK6 activates myocardial cell NF-kappaB and inhibits apoptosis in a p38 mitogen-activated protein kinase-dependent manner. J Biol Chem 1998; 273: 8232–8239.
Gaidano G, Ballerini P, Gong JZ, p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1991; 88: 5413–5417.
Elenitoba-Johnson KS, Jenson SD, Abbott RT, et al. Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc Natl Acad Sci USA 2003; 100 7259–7264.
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Kurosu, T., Takahashi, Y., Fukuda, T. et al. p38 MAP kinase plays a role in G2 checkpoint activation and inhibits apoptosis of human B cell lymphoma cells treated with etoposide. Apoptosis 10, 1111–1120 (2005). https://doi.org/10.1007/s10495-005-3372-z
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DOI: https://doi.org/10.1007/s10495-005-3372-z