E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes

Squamous differentiation of keratinocytes is associated with decreases in E 2F-1 mRNA expression and E2F activity, and these processes are disrupted in squamous cell carcinoma cell lines. We now show that E2F-1 mRNA expression is increased in primary squamous cell carcinomas of the skin relative to n ormal epidermis, To explore the relationship between E2F-1 and squamous dif ferentiation further, we examined the effect of altering E2F activity in pr imary human keratinocytes induced to differentiate. Promoter activity for t he proliferation-associated genes, cdc2 and keratin 14, are inhibited durin g squamous differentiation. This inhibition can be inhibited by overexpress ion of E2F-1 in keratinocytes, Overexpression of E2F-1 also suppressed the expression of differentiation markers (transglutaminase type 1 and keratin 10) in differentiated keratinocytes, Blocking E2F activity by transfecting proliferating keratinocytes with dominant negative E2F-1 constructs inhibit ed the expression of cdc2 and E2F-1, but did not induce differentiation. Fu rthermore, expression of the dominant negative construct in epithelial carc inoma cell lines and normal keratinocytes decreased expression from the cdc 2 promoter. These data indicate that E2F-1 promotes keratinocyte proliferat ion-specific marker genes and suppresses squamous differentiation-specific marker genes. Moreover, these data indicate that targeted disruption of E2F -1 activity may have therapeutic potential for the treatment of squamous ca rcinomas.