Protein interactions at Sp1-like sites in the TGF alpha promoter as visualized by in vivo genomic footprinting.

Abstract:

:Transcription from the rat TGF alpha promoter initiates at two predominant sites (-188 and -58) in a G+C-rich region that does not contain TATA or CAAT motifs. Previous studies using transfected reporter constructs implicated the transcription factor Sp1 in active expression from the promoter, particularly from the -58 site (Chen et al., 1992; Shin et al., 1992). In the present report we have examined the functionality of two adjacent clusters of Sp1-like recognition sites that are located in the upstream portion of the promoter from -300 to -273. A double-stranded oligonucleotide, which spanned this region and contained the putative Sp1 elements, demonstrated similar gel-mobility shifts in the presence of both crude HeLa cells nuclear extract and pure Sp1 protein. Mutations that simultaneously altered several of the overlapping Sp1 elements significantly reduced the gel-mobility shift activity of this oligonucleotide probe and, when introduced into the promoter templates, inhibited transcription in vitro from the proximal -188 start site. To confirm the binding of protein to these sites in cells, we carried out an in vivo genomic footprinting analysis of this portion of the TGF alpha promoter in normal and transformed rat liver epithelial cell lines that express the endogenous gene at varying levels. This analysis revealed clear evidence of protein/DNA interaction at Sp1-like sites in the -300 and -273 region in cells actively expressing the gene but not in a normal, parental cell line that expressed very low levels of TGF alpha mRNA. Collectively, these results corroborate the functional importance of Sp1 binding elements in the -300 to -273 region, and together with previous findings, indicate that two clusters of Sp1 binding sites respectively determine levels of transcription from the -188 and -58 start sites. Our additional finding that Sp1 mRNA and protein were present at similar levels in normal and transformed cells that expressed the endogenous TGF alpha gene at markedly different levels, suggests that the activity of the TGF alpha promoter could be regulated via the accessibility of Sp1 protein.

journal_name

Oncogene

journal_title

Oncogene

authors

Chen X,Wright KL,Berkowitz EA,Azizkhan JC,Ting JP,Lee DC

subject

Has Abstract

pub_date

1994-11-01 00:00:00

pages

3179-87

issue

11

eissn

0950-9232

issn

1476-5594

journal_volume

9

pub_type

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