ANALYSIS OF THE E-CADHERIN AND P-CADHERIN PROMOTERS IN MURINE KERATINOCYTE CELL-LINES FROM DIFFERENT STAGES OF MOUSE SKIN CARCINOGENESIS

We previously isolated the 5' upstream sequences of the mouse P-cadher in gene, in which putative binding sites for several transcription fac tors were identified between nt -101 and +30. In the study reported he re, the promoter activity of the postulated 5' cis-acting sequences of the P-cadherin promoter, and the activity of the proximal E-cadherin promoter were investigated in several murine keratinocyte cell lines s howing different levels of P- and E-cadherin expression as well as dif ferent morphology and tumorigenic behavior. Cell-type specificity and optimal activity of P-cadherin expression in murine keratinocytes was conferred by 5' sequences located between nt -200 and +30, and the CC- rich region (nt -101 to +80) and a CCAAT box element (nt -65) had a ma jor regulatory role. The cell-type specificity of the E-cadherin promo ter, on the other hand, was mediated by a combination of positive regu latory elements, a CC-rich region (nt -58 to -24), and a CCAAT box (nt -65) and repressor elements inside the E-pal sequence. Interestingly, the maximum repressor effect of the E-pal element was observed in non -expressing undifferentiated spindle cells. In vitro binding studies i ndicated that the CC-rich region of the P-cadherin promoter was mainly recognized by Sp1-related nuclear factors, whereas both AP2- and Sp1- related factors were involved in the interaction of the CC-rich region of the E-cadherin promoter. Common factors (probably related to the C P1 family) seemed also to be involved in the recognition of the CCAAT- box element of both the E- and P-cadherin promoters, but additional sp ecific factors participated in the interaction with the CCAAT box of t he E-cadherin promoter. Our studies also support the hypothesis that l oss or modification of some of the regulatory factors occurs during mo use skin tumor progression. (C) 1997 Wiley-Liss, Inc.