MEK6 regulates human involucrin gene expression via a p38 alpha- and p38 delta-dependent mechanism

A signaling cascade that includes protein kinase C (PKC), Ras, and MEKK1 re gulates involucrin (hINV) gene expression in epidermal keratinocytes (Efimo va, T., LaCelle, P., Welter, J. F., and Eckert, R. L. (1998) J. Biol. Chem. 273, 24387-24395 and Efimova, T., and Eckert, R. L. (2000) J. Biol. Chem. 275, 1601-1607). Because signal transfer downstream of MEKK1 may involve se veral MAPK kinases (MEKs), it is important to evaluate the regulatory role of each MEK isoform. In the present study we evaluate the role of MEK6 in t ransmitting this signal. Constitutively active MEK6 (caMEK6) increases hINV promoter activity and increases endogenous hINV levels. The caMER6-depende nt increase in gene expression is inhibited by the p38 MAPK inhibitor, SB20 3580, and is associated with a marked increase in p38 alpha MAPK activity; JNK and ERK kinases are not activated. In addition, hINV gene expression is inhibited by dominant-negative p38 alpha and increased when caMEK6 and p38 alpha are co-expressed. caMEK6 also activates p38 delta, but p38 delta inh ibits the caMEK6-dependent activation. These results suggest that MEK6 incr eases hINV gene expression by regulating the balance between activation of p38 alpha, which increases gene expression, and p38 delta, which decreases gene expression.