Targeted expression of c-Myc in the epidermis alters normal proliferation, differentiation and UV-B induced apoptosis.
c-Myc overexpression has been associated with several types of human cancers. To study the role of c-myc in epidermal differentiation and carcinogenesis, a transgenic mouse model was created to overexpress c-Myc in the epidermis. Human c-myc 2 cDNA was subcloned into a 6.5 kb mouse loricrin expression vector, ML.myc2. This loricrin promoter primarily directs expression in the epidermis in both proliferating and differentiated keratinocytes. On day 4, ML.myc2 transgenic pups develop a hyperkeratotic phenotype, which progressively worsens until day 7. Upon histological analysis, both hyperplasia and hyperkeratosis were evident. Bromodeoxyuridine (BrdU) incorporation revealed that transgenic mice had a threefold increase in the number of proliferating cells as compared with a normal littermate. Proliferative cells in the ML.myc2 epidermis were also found to be suprabasal, suggesting an inhibition of terminal differentiation in keratinocytes. Inhibition of terminal differentiation by c-Myc overexpression was further suggested by aberrant expression of differentiation markers, keratin 1, keratin 6, loricrin, and filaggrin in ML.myc2 transgenic mice. Interestingly, ML.myc2 keratinocytes exhibit a reduced sensitivity to UV-B induced apoptosis, in vivo. In vitro studies reveal the reduced sensitivity of ML.myc2 keratinocytes to UV-B irradiation is growth factor dependent. These findings provide evidence that overexpression of c-Myc in the epidermis induces proliferation, inhibits terminal differentiation and decreases the sensitivity of keratinocytes to UV-B induced apoptosis.
Waikel
R L
RL
Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, TX 77030, USA.
Wang
X J
XJ
Roop
D R
DR
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D004817:Epidermis / Q000473:pathology* / Q000528:radiation effects; D005260:Female; D000091344:Filaggrin Proteins; D016259:Genes, myc; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D006965:Hyperplasia; D007381:Intermediate Filament Proteins / Q000235:genetics; D007633:Keratins / Q000235:genetics; D007642:Keratosis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D014466:Ultraviolet Rays
D015415:Biomarkers; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D006133:Growth Substances; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; C064554:loricrin; D007633:Keratins