Transforming Growth Factor β1 Suppression of c-myc Gene Transcription: Role in Inhibition of Keratinocyte Proliferation

Transforming growth factor β 1 (TGF-β 1) is a potent growth inhibitor for many cell types, including most epithelial cells. However, the mechanism of growth inhibition is unknown. In skin keratinocytes, TGF-β 1 has been shown to inhibit growth and to rapidly reduce c-myc expression. It has been demonstrated that protein synthesis is required for TGF-β 1 regulation of c-myc in keratinocytes. Here we present evidence that treatment of mouse BALB/MK keratinocyte cells with either antisense c-myc oligonucleotides or TGF-β 1 inhibited cell entry into S phase. These results suggest that TGF-β inhibition of c-myc expression may be essential for growth inhibition by TGF-β 1. The block in c-myc expression by TGF-β 1 occurred at the level of transcriptional initiation. Studies with a series of 5' deletion c-myc/chloramphenicol acetyltransferase constructs indicated that a cis regulatory element(s), which resides between positions -100 and + 71 relative to P1 transcription start site, is responsible for the TGF-β 1 responsiveness. Based on these data, it is proposed that the mechanism of TGF-β 1 growth inhibition involves synthesis or modification of a protein that may interact with a specific element(s) in the 5' regulatory region of the c-myc gene, resulting in inhibition of transcriptional initiation.