Identification of heparin-binding EGF-like growth factor as a target in intercellular regulation of epidermal basal cell growth by suprabasal retinoic acid receptors

The role of retinoic acid receptors (RARs) in intercellular regulation of c ell growth was assessed by targeting a dominant-negative RAR alpha mutant ( dnRAR alpha) to differentiated suprabasal cells of mouse epidermis, dnRAR a lpha lacks transcriptional activation but not DNA-binding and receptor dime rization functions. Analysis of transgenic mice revealed that dnRAR alpha d ose-dependently impaired induction of basal cell proliferation and epiderma l hyperplasia by all-trans RA (tRA), dnRAR alpha formed heterodimers with e ndogenous retinoid X receptor-alpha (RXR alpha) over RA response elements i n competition with remaining endogenous RAR gamma-RXR alpha heterodimers, a nd dose-dependently impaired retinoid-dependent gene transcription, To iden tify genes regulated by retinoid receptors and involved in cell growth cont rol, we analyzed the retinoid effects on expression of the epidermal growth factor (EGF) receptor, EGF, transforming growth factor-a, heparin-binding EGF-like growth factor (HB-EGF) and amphiregulin genes, In normal epidermis , tRA rapidly and selectively induced expression of HB-EGF but not the othe rs. This induction occurred exclusively in suprabasal cells, In transgenic epidermis, dnRARa dose-dependently inhibited tRA induction of suprabasal HB -EGF and subsequent basal cell hyperproliferation, Together, our observatio ns suggest that retinoid receptor heterodimers located in differentiated su prabasal cells mediate retinoid induction of HB-EGF, which in turn stimulat es basal cell growth via intercellular signaling, These events may underlie retinoid action in epidermal regeneration during wound healing.