Inactivation of p38 MAPK during liver regeneration.
There is increasing evidence that p38 MAPK, which is classified as a stress-activated kinase, also participates in cell cycle regulation, functioning as a suppressor of cell proliferation and tumorigenesis. We conducted a study of p38 MAPK phosphorylation during liver regeneration in mice to determine whether p38 MAPK activation or inactivation may correlate with events that lead to DNA replication after partial hepatectomy (PH), and whether p38 MAPK activation may be required for hepatocyte DNA replication in vivo and in culture. We report that active p38 (Pi-p38 MAPK) is present in normal liver, is rapidly inactivated starting 30 min after PH, and is re-activated by 12h. Although levels of Pi-MKK 3/6, the upstream kinases that activate p38 MAPK increase after PH, the expression of the dual protein phosphatase 1 is also elevated, and may be responsible for Pi-p38 MAPK dephosphorylation after PH. Inactivation and re-activation of p38 MAPK inversely correlates with the stimulation of protein synthesis and translation pathways, as indicated by activation of p70S6 kinase, increases in the phosphorylation of initiation factor elF-4E and translational repressor, 4E-BP. The activity of a p38 MAPK downstream substrate, MAPKAPK2 (MK2), did not reflect the changing levels of Pi-p38 MAPK during liver regeneration. Pi-p38 MAPK may be involved in TNF-stimulated DNA replication of murine hepatocytes in culture, but is not necessary for hepatocyte DNA replication after PH. Our results suggest that p38 MAPK inactivation plays a permissible role in DNA replication during liver regeneration and is consistent with a role for p38 MAPK in the maintenance of hepatocyte cell cycle arrest in adult liver.
Campbell
Jean S
JS
Department of Pathology, University of Washington, School of Medicine, Seattle, WA 98195, USA. campjs@u.washington.edu
Argast
Gretchen M
GM
Yuen
Sebastian Y
SY
Hayes
Brian
B
Fausto
Nelson
N
D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis; D054637:Dual-Specificity Phosphatases / Q000096:biosynthesis; D004789:Enzyme Activation; D057075:Enzyme Assays; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000601:surgery; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D048069:Tumor Necrosis Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C110631:SB 220025; C505617:Dusp10 protein, mouse; C517020:Dusp1 protein, mouse