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Repression of transforming growth factor-beta receptor type I promoter expression by Sp1 deficiency.

Abstract
In this report, we describe the mechanism of TGF-beta receptor type I (RI) repression in the GEO human colon carcinoma cells. Treatment of GEO cells with the DNA methyltransferase inhibitor, 5 azacytidine induced RI expression and restored TGF-beta response. A stably transfected RI promoter-reporter construct (RI-Luc) expressed higher activity in the 5 aza C treated GEO cells, suggesting the activation of a transactivator for RI transcription. Gel shift analysis indicated enhanced binding of proteins from the 5 aza C treated nuclear extracts to radiolabeled Sp1 oligonucleotides specifically contained in the RI promoter. Protein stability studies after cyclohexamide treatment suggested an increase in the Sp1 protein stability from the 5 aza C treated GEO cells. Further, transfection of Sp1 cDNA into untreated GEO control cells increased RI promoter activity and thus induced RI expression. 5 aza C mediated Sp1 expression in Sp1 deficient GEO colon and MCF-7 breast cancer cells also enhanced the activity of several other Sp1 dependent promoters such as TGF-beta receptor type II (RII), Cyclin A and p21/waf1/cip1. These results indicate that restoration of Sp1 in several different types of Sp1 deficient cells leads to enhanced activation of a wide range of Sp1 dependent promoters.
AuthorsS Periyasamy, S Ammanamanchi, M P Tillekeratne, M G Brattain
JournalOncogene (Oncogene) Vol. 19 Issue 40 Pg. 4660-7 (Sep 21 2000) ISSN: 0950-9232 [Print] England
PMID11030155 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antimetabolites, Antineoplastic
  • CDKN1A protein, human
  • Cyclin A
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • Sp1 Transcription Factor
  • DNA (Cytosine-5-)-Methyltransferases
  • Protein Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Azacitidine
Topics
  • Activin Receptors, Type I
  • Adenocarcinoma (genetics, metabolism, pathology)
  • Antimetabolites, Antineoplastic (pharmacology)
  • Azacitidine (pharmacology)
  • Breast Neoplasms (genetics, metabolism, pathology)
  • Colonic Neoplasms (genetics, metabolism, pathology)
  • Cyclin A (biosynthesis, genetics)
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins (biosynthesis, genetics)
  • DNA (Cytosine-5-)-Methyltransferases (antagonists & inhibitors)
  • DNA Methylation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Neoplasm Proteins (biosynthesis, deficiency, genetics, physiology)
  • Promoter Regions, Genetic (genetics)
  • Protein Serine-Threonine Kinases (biosynthesis, genetics)
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta (biosynthesis, genetics)
  • Recombinant Fusion Proteins (physiology)
  • Sp1 Transcription Factor (deficiency, physiology)
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured (drug effects, metabolism)

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