PMID- 8876223 OWN - NLM STAT- MEDLINE DCOM- 19961204 LR - 20190501 IS - 0027-8424 (Print) IS - 1091-6490 (Electronic) IS - 0027-8424 (Linking) VI - 93 IP - 21 DP - 1996 Oct 15 TI - Transcription factor EGR-1 suppresses the growth and transformation of human HT-1080 fibrosarcoma cells by induction of transforming growth factor beta 1. PG - 11831-6 AB - The early growth response 1 (EGR-1) gene product is a transcription factor with role in differentiation and growth. We have previously shown that expression of exogenous EGR-1 in various human tumor cells unexpectedly and markedly reduces growth and tumorigenicity and, conversely, that suppression of endogenous Egr-1 expression by antisense RNA eliminates protein expression, enhances growth, and promotes phenotypic transformation. However, the mechanism of these effects remained unknown. The promoter of human transforming growth factor beta 1 (TGF-beta 1) contains two GC-rich EGR-1 binding sites. We show that expression of EGR-1 in human HT-1080 fibrosarcoma cells uses increased secretion of biologically active TGF-beta 1 in direct proportion (rPearson = 0.96) to the amount of EGR-1 expressed and addition of recombinant human TGF-beta 1 is strongly growth-suppressive for these cells. Addition of monoclonal anti-TGF-beta 1 antibodies to EGR-1-expressing HT-1080 cells completely reverses the growth inhibitory effects of EGR-1. Reporter constructs bearing the EGR-1 binding segment of the TGF-beta 1 promoter was activated 4- to 6-fold relative to a control reporter in either HT-1080 cells that stably expressed or parental cells cotransfected with an EGR-1 expression vector. Expression of delta EGR-1, a mutant that cannot interact with the corepressors, nerve growth factor-activated factor binding proteins NAB1 and NAB2, due to deletion of the repressor domain, exhibited enhanced transactivation of 2- to 3.5-fold over that of wild-type EGR-1 showing that the reporter construct reflected the appropriate in vivo regulatory context. The EGR-1-stimulated transactivation was inhibited by expression of the Wilms tumor suppressor, a known specific DNA-binding competitor. These results indicate that EGR-1 suppresses growth of human HT-1080 fibrosarcoma cells by induction of TGF-beta 1. FAU - Liu, C AU - Liu C AD - Sidney Kimmel Cancer Center, San Diego, CA 92121, USA. FAU - Adamson, E AU - Adamson E FAU - Mercola, D AU - Mercola D LA - eng GR - CA 63783/CA/NCI NIH HHS/United States GR - CA 6788/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (DNA-Binding Proteins) RN - 0 (EGR1 protein, human) RN - 0 (Early Growth Response Protein 1) RN - 0 (Immediate-Early Proteins) RN - 0 (Recombinant Proteins) RN - 0 (Transcription Factors) RN - 0 (Transforming Growth Factor beta) RN - EC 2.3.1.28 (Chloramphenicol O-Acetyltransferase) SB - IM MH - Binding Sites MH - Cell Differentiation MH - Cell Division/drug effects MH - Cell Line MH - Chloramphenicol O-Acetyltransferase/biosynthesis MH - DNA-Binding Proteins/biosynthesis/*physiology MH - Early Growth Response Protein 1 MH - Fibrosarcoma MH - Genes, Reporter MH - Genetic Vectors MH - Humans MH - *Immediate-Early Proteins MH - Kinetics MH - Phenotype MH - Promoter Regions, Genetic MH - Recombinant Proteins/metabolism/pharmacology MH - Transcription Factors/biosynthesis/*physiology MH - Transforming Growth Factor beta/*biosynthesis/*pharmacology MH - Tumor Cells, Cultured MH - Zinc Fingers PMC - PMC38144 EDAT- 1996/10/15 00:00 MHDA- 1996/10/15 00:01 PMCR- 1997/04/15 CRDT- 1996/10/15 00:00 PHST- 1996/10/15 00:00 [pubmed] PHST- 1996/10/15 00:01 [medline] PHST- 1996/10/15 00:00 [entrez] PHST- 1997/04/15 00:00 [pmc-release] AID - 10.1073/pnas.93.21.11831 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11831-6. doi: 10.1073/pnas.93.21.11831.