UVB-induced apoptosis in normal human keratinocytes: role of the erbB receptor family.
Exposure of human keratinocytes to ultraviolet B (UVB) light leads to the activation of a variety of cell-surface receptors; however, the biologic consequences of these activated receptors are still unclear. It was previously reported that inhibition of cellular tyrosine kinase activity suppressed UVB-dependent effects in human skin. We confirmed that the same suppression of UVB-induced apoptosis occurs in normal human keratinocytes grown in culture. Furthermore, we sought to determine the role of erbB receptor tyrosine kinases in human keratinocytes following UVB irradiation. Using a specific inhibitor of the erbB family of tyrosine kinase receptors, DAPH, we investigated the effects of UVB-dependent activation of these receptors on keratinocyte biology. The addition of DAPH to keratinocytes resulted in the concentration-dependent protection of UVB-induced apoptosis. The protection from apoptosis was not due to the induction of keratinocyte differentiation, the loss of keratinocyte viability, or inhibition of the proliferative potential of keratinocytes by DAPH. The effect of DAPH on apoptosis was specific for UVB as it had no effect on bleomycin-induced apoptosis. Furthermore, the inhibition of UVB-induced apoptosis could also be observed using neutralizing antibodies to either erbB1 or erbB2. Finally, we demonstrated that DAPH could also inhibit UVB-induced apoptosis in an epidermal organotypic model system. These studies suggest an important role for the erbB receptors in UVB-induced apoptosis of human keratinocytes.
Lewis
Davina A
DA
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Hurwitz
Steven A
SA
Spandau
Dan F
DF
D000906:Antibodies / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism / Q000528:radiation effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000378:metabolism / Q000528:radiation effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000528:radiation effects*; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D008297:Male; D009924:Organ Culture Techniques; D010797:Phthalimides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000528:radiation effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects*
D000906:Antibodies; D016588:Anticarcinogenic Agents; D053148:Caspase 3; D020169:Caspases; D066246:ErbB Receptors; D019833:Genistein; D010797:Phthalimides; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C117146:4,5-bis(4-fluoroanilino)phthalimide; C407689:6,7-dimethoxy-2-phenylquinoxaline; C505407:CASP3 protein, human