Differential regulation of EGF-like growth factor genes in human keratinocytes

ErbB signaling increases protein levels of multiple EGF-like growth factors in epithelial cells. To better understand this process, we examined the effects of EGF receptor stimulation on the transcription and mRNA stability of TGF-alpha, amphiregulin (AR), and heparin-binding EGF-like growth factor (HB-EGF) in human keratinocytes. EGF stimulation increased transcription of TGF-alpha, AR, and HB-EGF by 3- to 4-fold within 1 to 2 h. However, AR and HB-EGF mRNA levels peaked at 2 h and then rapidly declined, whereas TGF-alpha transcripts remained elevated for at least 6 h. Actinomycin D decay experiments yielded the rank order of transcript stability TGF-alpha > AR > HB-EGF. Interestingly, ligand treatment appeared to stabilize TGF-alpha and AR mRNAs, whereas HB-EGF transcripts were destabilized. These data demonstrate that gene-specific alterations in gene transcription and mRNA stability play important roles in the temporal regulation of EGF-like growth factor gene expression.