Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway.
The mitogen-activated protein kinase (MAPK) cascade is believed to function as an important regulator of prostaglandin biosynthesis. Previously we reported that interleukin-1beta induces activation of JNK/SAPK and p38 MAPK with concomitant up-regulation of cyclooxygenase (Cox)-2 expression and prostaglandin E2 (PGE2) synthesis. Our experiments demonstrate that overexpression of DeltaMEKK1 (a constitutively active truncation mutant of MEKK1 containing the C-terminal 324 amino acids) increases Cox-2 expression and PGE2 production which is completely blocked by SC68376, a pharmacologic inhibitor of p38 MAPK. DeltaMEKK1 overexpression results in activation of both c-Jun N-terminal kinases/extracellular signal-regulated kinases (JNK/SAPK) and p38 MAPK. Furthermore, activation of MEKK1 increases SEK1/MKK4 but not MKK3 or MKK6 activity. These findings suggest that MEKK1 --> SEK1/MKK4 may function as an upstream kinase capable of activating both p38 MAPK and JNK/SAPK with subsequent induction of Cox-2 expression and PGE2 production. We also found that overexpression of the constitutively active form of SEK1 (SEK1-ED) increases both p38 MAPK and JNK/SAPK phosphorylation, and increases PGE2 production and Cox-2 expression. By comparison, overexpression of the dominant negative form of SEK1 (SEK1-AL) decreases the phosphorylation of both p38 MAPK and JNK/SAPK and reduces Cox-2 expression. Together, this data suggests a potential role for the MEKK1 --> SEK1/MKK4 --> p38 MAPK -->--> Cox-2 cascade linking members of the MAPK pathway with prostaglandin biosynthesis.
Guan
Z
Z
Department of Molecular Biology and Pharmacology and Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Buckman
S Y
SY
Pentland
A P
AP
Templeton
D J
DJ
Morrison
A R
AR
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D004789:Enzyme Activation; D004790:Enzyme Induction; D007527:Isoenzymes / Q000096:biosynthesis*; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone