ARSENATE PERTURBATION OF HUMAN KERATINOCYTE DIFFERENTIATION

Treatment of cultured malignant human keratinocytes with sodium arsena te greatly suppressed expression of involucrin, a specific marker of k eratinocyte differentiation. This action was primarily attributable to inhibition of involucrin transcription according to message run-on an d stability measurements. Involucrin was suppressed in nontumorigenic keratinocytes as well, although the efficacy of suppression was less d ramatic in cells derived from clinically normal epidermis, Several tra nsition metal oxyanions (vanadate, molybdate, and tungstate) also subs tantially suppressed involucrin expression, but okadaic acid was ineff ective. Immunoblotting detected marked increases in tyrosine phosphory lation of several proteins as a consequence of arsenate treatment of t he cultures, while mobility shift analysis revealed a dramatic loss of DNA binding by the transcription factor AP2. These findings support a proposed role for altered levels of protein tyrosine phosphorylation in keratinocyte differentiation. They also suggest that arsenate pertu rbs the differentiation program in target cells by altering this phosp horylation level and transcription factor activity.