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 cell growth was assessed by targeting a dominant-negative RAR alpha mutant (dnRAR alpha) to differentiated suprabasal cells of mouse epidermis, dnRAR alpha lacks transcriptional activation but not DNA-binding and receptor dimerization functions. Analysis of transgenic mice revealed that dnRAR alpha dose-dependently impaired induction of basal cell proliferation and epidermal hyperplasia by all-trans RA (tRA), dnRAR alpha formed heterodimers with endogenous retinoid X receptor-alpha (RXR alpha) over RA response elements in competition with remaining endogenous RAR gamma-RXR alpha heterodimers, and dose-dependently impaired retinoid-dependent gene transcription, To identify genes regulated by retinoid receptors and involved in cell growth control, 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 others. 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 observations suggest that retinoid receptor heterodimers located in differentiated suprabasal cells mediate retinoid induction of HB-EGF, which in turn stimulates basal cell growth via intercellular signaling, These events may underlie retinoid action in epidermal regeneration during wound healing.