Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation.
Transforming growth factor beta 1 (TGF-beta 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-beta 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-beta 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-beta 1 inhibited cell entry into S phase. These results suggest that TGF-beta inhibition of c-myc expression may be essential for growth inhibition by TGF-beta 1. The block in c-myc expression by TGF-beta 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-beta 1 responsiveness. Based on these data, it is proposed that the mechanism of TGF-beta 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.
Pietenpol
J A
JA
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.
Holt
J T
JT
Stein
R W
RW
Moses
H L
HL
D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc; D011519:Proto-Oncogenes / Q000187:drug effects*; D015183:Restriction Mapping; D013489:Suppression, Genetic / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D015291:Transforming Growth Factors / Q000494:pharmacology*
D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D015291:Transforming Growth Factors; D015500:Chloramphenicol O-Acetyltransferase; D011505:Protein-Tyrosine Kinases