INVOLVEMENT OF C-JUN IN THE REGULATION OF TERMINAL DIFFERENTIATION GENES IN NORMAL AND MALIGNANT KERATINOCYTES

In stratifying cultures of human keratinocytes, expression of the prot o-oncoprotein c-JUN and the small proline rich 2 (SPRR2) protein, a pr ecursor of the cornified cell envelope, are inversely related. Whereas c-JUN is typically found in basal proliferating cells, SPRR2 is restr icted to suprabasal differentiating layers. Malignant keratinocytes (d erived from squamous cell carcinoma, SCC) have reduced sprr2 expressio n, consistent with their low potential to differentiate, and express c -jun at higher levels than normal keratinocytes. A direct relation bet ween c-jun and sprr2 expression was shown in several ways: transient e ctopic expression of c-jun inhibits sprr2a promoter activity in normal differentiating cells, whereas in malignant keratinocytes a dominant negative c-jun mutant restored at least partially both the low promote r activity and the expression of endogenous sprr2. These effects are m ediated via a 134 bp promoter fragment which does not include the sprr 2a AP-1 binding site. Interestingly, in an SCC cell line, constitutive ly expressing the dominant c-jun mutant, expression of the terminal di fferentiation marker involucrin is also strongly increased, suggesting that c-JUN is a general modulator of keratinocyte terminal differenti ation rather than only affecting the expression of sprr2.