Retinoids are essential for normal epidermal growth and differentiation and
show potential for the prevention or treatment of various epithelial neopl
asms. The retinoic acid receptors (RAR alpha, -beta, and -gamma) are transd
ucers of the retinoid signal. The epidermis expresses RAR gamma and RAR alp
ha, both of which are potential mediators of the effects of retinoids in th
e epidermis. To further investigate the role(s) of these receptors, we deri
ved transformed keratinocyte lines from wild-type, RAR alpha RAR gamma, and
RAR alpha gamma null mice and investigated their response to retinoids, in
cluding growth inhibition, markers of growth and differentiation, and AP-1
activity. Our results indicate that RAR gamma is the principle receptor con
tributing to all-trans-retinoic acid (RA)-mediated growth arrest in this sy
stem. This effect partially correlated with inhibition of AP-1 activity. in
the absence of RARs, the synthetic retinoid N-(4-hydroxyphenyl)-retinamide
inhibited growth; this was not observed with Rtl 9-cis RA, or the syntheti
c retinoid (E)-4-[2-(5, 5, 8, 8 tetramethyl-5,6,7,8-tetrahydro-2- naphthale
nyl)-1-propenyl] benzoic acid. Finally, both RAR alpha and RAR gamma differ
ently affected the expression of some genes suggesting both specific and ov
erlapping roles for the RARs in keratinocytes.