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  • The EMBO Journal (1999) 18, 1539 - 1548
  • doi:10.1093/emboj/18.6.1539

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

Jia-Hao Xiao2,8, Xu Feng3,8, Wen Di4, Zhen-Hui Peng5, Lih-Ann Li6, Pierre Chambon7 and John J. Voorhees1

  1. Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA
  2. Present address: Allergen Inc., PO Box 19534, 2525 DuPont Drive, Irvine, CA 92623-9534, USA
  3. Present address: Building 10/Room 8D04, NIH/NDDK/MCEB, Bethesda, MD 20892, USA
  4. Present address: Department of Obstetrics and Gynecology, Ren-Ji Hospital, Shanghai Second Medical University, 200001 Shanghai, People's Republic of China
  5. Present address: Department of Dermatology, Xi-An Medical University, 710004 Xi-An, People's Republic of China
  6. Present address: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 11529
  7. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Collège de France, 67404 Illkirch, France
  8. J.H.Xiao and X.Feng contributed equally to this work

Correspondence to:

Jia-Hao Xiao, E-mail: Xiao_Jia-Hao@Allergan.com

Received 10 November 1998; Accepted 19 January 1999; Revised 19 January 1999

The role of retinoic acid receptors (RARs) in intercellular regulation of cell growth was assessed by targeting a dominant-negative RARalpha mutant (dnRARalpha) to differentiated suprabasal cells of mouse epidermis. dnRARalpha lacks transcriptional activation but not DNA-binding and receptor dimerization functions. Analysis of transgenic mice revealed that dnRARalpha dose-dependently impaired induction of basal cell proliferation and epidermal hyperplasia by all-trans RA (tRA). dnRARalpha formed heterodimers with endogenous retinoid X receptor-alpha (RXRalpha) over RA response elements in competition with remaining endogenous RARgamma–RXRalpha 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-alpha, 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, dnRARalpha 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.

  • Keywords:

    • cell proliferation,
    • epidermis,
    • HB-EGF,
    • retinoid X receptor,
    • transgenic mouse