Abstract
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.
Highlights
From the Cell Biology Section, Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Diangle Park,North Carolina 27709
To study the action of IFN-y on squamous cell differentiation in NHEK cells, we examined its effect on two stages of this differentiation process, irreversible growth arrest andexpression of the squamous phenotype
The inhibition of cell proliferation by IFN-y was an irreversible process since removal of IFN-y from the medium 3 h after addition failed to restore proliferation. This was confirmed by the observed reduction in thecolony forming efficiency of NHEK cells from 43%to 50.1% afterIFN-y treatment (Table I). These results indicate that IFN-y commits NHEK cells to a state of irreversible growth arrest
Summary
A variety of factors including activators of protein kidifferentiation in normal human epidermal keratino- nase C, calcium ions, retinoids,and transforminggrowth factor cytes This induction is characterizedbya 295% decrease in the mRNA levelof two growth regulatory genes, cdc and E2F-1, and a 7-16-fold increase in the expression oftwo squamous cell-specific genes, transglutaminase type I and cornifin. In contrast to the decrease in cdc and E2F-1 expression, the increase in transglutaminase type I and cornifin mRNAs b y IFN-y 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-y on the expression of squamous cell-specific genes is antagonized by retinoic acid and transforming growth factor pl Both factors are potent suppressorsof the induction of transglutaminase type I and cornifin; they do not.
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