Prosurvival and proapoptotic functions of ERK1/2 activation in murine thymocytes in vitro.
The extracellular signal-regulated kinases 1/2 (ERK1/2) are serine/threonine-selective protein kinases involved in proliferation and differentiation of cells, including thymocytes. The requirement of ERK1/2 for thymocyte differentiation and maturation has been well established; however, their role in regulating thymocyte survival and apoptosis has not been resolved. Here, we asked whether ERK1/2 affected thymocyte survival in vitro in response to apoptotic stimuli. The results show that phorbol 12-myristate 13-acetate (PMA) treatment (with or without ionomycin) and serum starvation (s/s) induced sustained ERK1/2 activation in murine thymocytes. Importantly, pharmacological treatment of thymocytes with the MEK inhibitor UO126 revealed that PMA-induced ERK1/2 activation was proapoptotic, whereas serum starvation-induced ERK1/2 activation inhibited apoptosis and promoted cell survival. While basal MEK activity was required for both s/s- and PMA-induced ERK1/2 activation, MEK activity increased only in response to PMA. The results show that the suppression of ERK1/2 phosphatases was responsible for s/s-induced sustained ERK1/2 activation. Unexpectedly, neither s/s-induced proapoptotic nor PMA-induced anti-apoptotic functions of ERK1/2 depended on the Bcl-2 family phosphoprotein Bim(EL), which was previously implicated in thymocyte apoptosis. Lastly, etoposide treatment of immature thymocytes induced both p53 and ERK1/2 activation, but ERK1/2 activity did not affect the phosphorylation and stabilization of p53. Thus, ERK1/2 has a dual role in promoting cell survival and cell death in thymocytes in the context of different stimuli.
Smirnova
Irina S
IS
Dept. Biology, University of Texas at San Antonio, San Antonio, TX 78249, United States.
Chang
Steve
S
Forsthuber
Thomas G
TG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002070:Butadienes / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002070:Butadienes; D008565:Membrane Proteins; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate