Transforming growth factor beta 1 suppression of c-myc gene transcription: role in inhibition of keratinocyte proliferation.

Pietenpol JA, Holt JT, Stein RW, Moses HL
Proc Natl Acad Sci U S A. 1990 87 (10): 3758-62

PMID: 2187192 · PMCID: PMC53982 · DOI:10.1073/pnas.87.10.3758

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.

MeSH Terms (22)

Animals Base Sequence Cell Division Cell Nucleus Cells, Cultured Chloramphenicol O-Acetyltransferase DNA Replication Gene Expression Keratinocytes Mice Mice, Inbred BALB C Molecular Sequence Data Oligodeoxyribonucleotides Protein-Tyrosine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-myc Proto-Oncogenes Restriction Mapping Suppression, Genetic Transcription, Genetic Transfection Transforming Growth Factors

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