Aj. Dicker et al., E2F-1 induces proliferation-specific genes and suppresses squamous differentiation-specific genes in human epidermal keratinocytes, ONCOGENE, 19(25), 2000, pp. 2887-2894
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.