Induction of prostaglandin endoperoxide synthase 2 by mitogen-activated protein kinase cascades

Prostaglandin endoperoxide synthase (PGHS) catalyses the rate-limiting step in the formation of prostaglandin and thromboxane eicosanoids from arachid onic acid released by phospholipase A,. Two forms of PGHS exist, PGHS-1 and PGHS-2. PGHS-2, normally absent from cells, is rapidly expressed in respon se to a wide variety of stimuli and has been implicated in the pathogenesis of colon cancer and several inflammatory diseases. The three principal mit ogen-activated protein kinase (MAPK) pathways are the extracellular signal- regulated protein kinase (ERK), the c-Jun N-terminal kinase (JNK) cascade a nd the p38-MAPK cascade. The present study was undertaken to investigate th e putative involvement of the MAPK cascades in PGHS-2 induction. The potent ial role of ERK in PGHS-2 up-regulation was assessed by using cell lines ex pressing, both stably and after adenoviral infection, constitutively active forms of its upstream activator MAPK/ERK kinase (MEK1). The possible invol vement of JNK and p38-MAPK in positively modulating PGHS-2 transcription wa s investigated by using adenovirus-mediated transfer of active forms of the ir respective specific upstream kinases, mitogen-activated protein kinase k inase (MKK) 7 and MKK3/MKK6. ERK activation promoted the induction of PGHS- 2 mRNA and protein. Similarly, activation of JNK by Ad-MKK7D and p38-MAPK b y Ad-MKK3bE/Ad-MKK6bE resulted in the increased expression of PGHS-2. These results provide evidence that activation of all three of the major mammali an MAPK leads to the induction of PGHS-2 mRNA and protein. Because PGHS-2 i s up-regulated by a diverse range of stimuli, both mitogenic and stress-evo king, these results provide evidence that the convergence point of these st imuli could be the activation of one or more MAPK cascade(s).