THE INDUCTION OF TERMINAL DIFFERENTIATION MARKERS BY THE CAMP PATHWAYIN HUMAN HACAT KERATINOCYTES

The terminal differentiation of human epidermal keratinocytes is a com plex morphological and biochemical shift from a mitotically active cel l to an inert protein cross-licked envelope, This transition is a clea rly predetermined cell death mechanism, but it is unlike many other pr ogrammed cell deaths in that it is not apoptotic, To explore and contr ast the mechanism by which keratinocytes are committed to differentiat ion rather than apoptosis, we focused on the cyclic adenosine monophos phate (cAMP) signaling pathway using selective modulators of intracell uar cAMP levels, Markers of differentiation were assayed by Western bl otting, Raising intracelluar cAMP levels by treating HaCaT. cells with forskol in, a diterpene, or with isobutylmethylxanthine, a phosphodie sterase inhibitor, and isoproterenol, a beta-adrenergic receptor agoni st that selectively activates adenylate cyclase, increased the levels of the differentiation markers keratin K1 and K10, involucrin and tran sglutaminase, H89 and KT5720, both inhibitors of cAMP-dependent protei n kinase. sup pressed the expression of keratins KI and K10, These obs ervations are in line with the defined role for cAMP in the control of keratinocyte differentiation.