Control of growth regulatory and differentiation-specific genes in human epidermal keratinocytes by interferon gamma. Antagonism by retinoic acid and transforming growth factor beta 1.
Interferon gamma (IFN-gamma) is a potent inducer of squamous differentiation in normal human epidermal keratinocytes. This induction is characterized by a > or = 95% decrease in the mRNA level of two growth regulatory genes, cdc2 and E2F-1, and a 7-15-fold increase in the expression of two squamous cell-specific genes, transglutaminase type I and cornifin. In contrast to the decrease in cdc2 and E2F-1 expression, the increase in transglutaminase type I and cornifin mRNAs by IFN-gamma occurs after a lagtime of more than 12 h. These results are consistent with the hypothesis that in normal human epidermal keratinocyte cells irreversible growth arrest precedes the expression of the squamous-differentiated phenotype. The action of IFN-gamma on the expression of squamous cell-specific genes is antagonized by retinoic acid and transforming growth factor beta 1. Both factors are potent suppressors of the induction of transglutaminase type I and cornifin; however, they do not prevent the commitment to irreversible growth arrest. Several squamous cell carcinoma cell lines do not show a detectable decrease in cdc2 or increase in transglutaminase type I mRNA levels after IFN-gamma treatment and appear to be altered in their control of squamous differentiation.
Saunders
N A
NA
Cell Biology Section, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709.
Jetten
A M
AM
D016203:CDC2 Protein Kinase / Q000096:biosynthesis* / Q000235:genetics; D002294:Carcinoma, Squamous Cell; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D055233:Cornified Envelope Proline-Rich Proteins; D015342:DNA Probes; D005786:Gene Expression Regulation / Q000187:drug effects*; D006133:Growth Substances / Q000096:biosynthesis*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D012878:Skin Neoplasms; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D011503:Transglutaminases / Q000096:biosynthesis / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D055233:Cornified Envelope Proline-Rich Proteins; D015342:DNA Probes; D006133:Growth Substances; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D007371:Interferon-gamma; D011503:Transglutaminases; D016203:CDC2 Protein Kinase