Stable induction of c-jun mRNA expression in normal human keratinocytes by agents that induce predifferentiation growth arrest.
A variety of agents can induce predifferentiation growth arrest (PGA) in human keratinocytes; these include transforming growth factor beta 1 (TGF-beta 1) and razoxane. We evaluated the ability of these and other agents to induce the expression of a variety of transcription factor genes including c-fos, c-myc, junB, and c-jun. The results show that both TGF-beta 1 and razoxane induce maximal c-jun mRNA expression 4 days after initiation of treatment concurrent with the development of PGA. In contrast, no detectable induction of c-fos, c-myc, or junB was observed. Keratinocytes maintained in the presence of TGF-beta 1 for an additional 3 days continued to show high levels of c-jun mRNA, indicating stable induction. Razoxane treatment also induces PGA and high c-jun mRNA levels for 4 days, but thereafter a decay of c-jun expression occurs. Run-off transcription experiments comparing rapidly growing cells with cells treated with TGF-beta 1 for 4 days demonstrated a significant increase in transcriptional activity of the c-jun gene. This result indicates that the increase in c-jun gene expression is due in part to a change in transcriptional regulation of c-jun. The stable induction of c-jun mRNA in keratinocytes at the PGA state is unique because the induction of this gene is usually transient. The finding that c-fos is not coinduced suggests that c-Jun homodimers or other AP-1 heterodimers may be formed at the PGA state to facilitate the stable induction of c-jun mRNA. This experimental system should therefore serve as a model system to study the molecular mechanisms for the stable control of c-jun gene expression and the control of AP-1-dependent gene expression during the process of keratinocyte differentiation.
Blatti
S P
SP
Department of Pathology, University of Tennessee Medical School, Memphis 38163.
Scott
R E
RE
D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016758:Genes, jun / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007399:Interphase / Q000187:drug effects; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D011519:Proto-Oncogenes / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis*; D011929:Razoxane / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D007328:Insulin; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D011929:Razoxane; D004815:Epidermal Growth Factor; D013755:Tetradecanoylphorbol Acetate