STAT5a/PPARgamma pathway regulates involucrin expression in keratinocyte differentiation.

Signal transducers and activators of transcription (STATs) are critical to growth factor-mediated intracellular signal transduction. We observed the rapid expression and activation of STAT5a during keratinocyte differentiation induced by suspension culture. STAT5a expression preceded that of involucrin, an important molecule in the terminal differentiation of keratinocytes. To determine whether STAT5a regulated involucrin expression, we expressed a dominant-negative (dn) STAT5a that blocks the dimerization of STAT5 and inhibits its nuclear translocation. We found that dn-STAT5a inhibited involucrin expression in keratinocytes. Given that STAT5 regulates adipogenesis via activating the peroxisome proliferator-activated receptor (PPAR) gamma signal, we hypothesized that STAT5a regulated involucrin expression in the same manner. To test this hypothesis, we examined the expression and transactivation of PPARgamma in a suspension culture of keratinocytes. Suspension culture induced PPARgamma expression and triggered PPARgamma transactivation rapidly and dn-STAT5a downregulated this induction and suppressed PPARgamma transactivation. Furthermore, preincubation with the PPARgamma/retinoid X-receptor inhibitor HX-531 or the introduction of a dn-PPARgamma prevented the activation of involucrin promoter and inhibited its induction. This report provides early evidence of a major role for STAT5a in the differentiation of keratinocytes, where it contributes to involucrin expression by activating the PPARgamma signal.