Induction of cyclooxygenase-2 by the activated MEKK1 → SEK1/MKK4 → p38 mitogen-activated protein kinase pathway

Zhonghong Guan, Sha Avhree Y. Buckman, Alice P. Pentland, Dennis J. Templeton, Aubrey R. Morrison

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The mitogen-activated protein kinase (MAPK) cascade is believed to function as an important regulator of prostaglandin biosynthesis. Previously we reported that interleukin-1β 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 AMEKK1 (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. AMEKK1 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 NK/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.

Original languageEnglish
Pages (from-to)12901-12908
Number of pages8
JournalJournal of Biological Chemistry
Issue number21
StatePublished - May 22 1998


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