Staurosporine induces a complete program of terminal differentiation in neoplastic mouse keratinocytes via activation of protein kinase C

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Abstract
Staurosporine (stsp) is a kinase inhibitor which induces cornified envelope assembly and terminal differentiation in normal and neoplastic mouse keratinocytes. In the tumorigenic cell lines 308 and SP-1 experiments were performed to determine if this effect was due only to activation of transglutaminases (TGases) already residing within the cell, or whether stsp was capable of inducing a full program of differentiation. Assessment of keratinocyte differentiation-specific protein expression in neoplastic cells revealed that expression of the suprabasal marker SPR-1 and the granular markers loricrin and filaggrin were induced by stsp. Protein expression was controlled by changes in mRNA expression, determined by Northern blotting. Transcripts for the TGase isoforms TGK and TGE were also induced by stsp in SP-1 cells, whereas only TGK expression was increased in 308 cells, which appear not to express TGE. Protein kinase C(PKC) activation is required for differentiation in normal mouse keratinocytes. To determine if stsp induces differentiation in neoplastic cells by regulation of this signaling pathway cells were treated with the specific PKC inhibitor GF 109203X or with different concentrations of bryostatin 1 to down-regulate specific isoforms of PKC prior to and during treatment with stsp. Stsp-induced protein cross-linking and marker expression were inhibited by GF 109203X, suggesting paradoxical activation of PKC by stsp. PKC αε and δ, but not PKCη and ζ, were down-regulated bytreating both cell types with bryostatin; pre-treatment of cells with bryostatin inhibited stsp-induced protein cross-linking and marker expression, suggesting a necessity or the α,δand/orεisoforms in stsp-induced differentiation.

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