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PMID: 2187192 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 87 ·No. 10 ·1990-05-00 ·Pages 3758-62

Pietenpol JA, Holt JT, Stein RW, Moses HL

Abstract

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
Animals Base Sequence Cell Division/drug effects Cell Nucleus/drug effects,metabolism Cells, Cultured Chloramphenicol O-Acetyltransferase/genetics DNA Replication/drug effects Gene Expression/drug effects Keratinocytes/cytology,drug effects,enzymology Mice Mice, Inbred BALB C Molecular Sequence Data Oligodeoxyribonucleotides/pharmacology Protein-Tyrosine Kinases/genetics Proto-Oncogene Proteins/genetics Proto-Oncogene Proteins c-myc Proto-Oncogenes/drug effects Restriction Mapping Suppression, Genetic/drug effects Transcription, Genetic/drug effects Transfection Transforming Growth Factors/pharmacology
Chemicals
Oligodeoxyribonucleotides Proto-Oncogene Proteins Proto-Oncogene Proteins c-myc Transforming Growth Factors Chloramphenicol O-Acetyltransferase Protein-Tyrosine Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Pietenpol J A
Department of Cell Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.
Holt J T
Stein R W
Moses H L
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.87.10.3758
Published
1990-05-00
Pages
3758-62
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC53982
Subset
IM
Grants
NCI NIH HHS · CA 09592 · United States
NCI NIH HHS · CA 42572 · United States
NCI NIH HHS · CA 49052 · United States
External Links
PubMed source DOI: 10.1073/pnas.87.10.3758 PMC Full Text View journal details
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