Transcriptional and post-transcriptional induction of the TGFalpha gene in transformed rat liver epithelial cells.

Abstract:

:Although TGFalpha mRNA and protein are frequently elevated in neoplastic cells, neither the level at which deregulation occurs nor the mechanism(s) responsible have been well characterized. As a first step, we examined the induction of TGFalpha mRNA in two series of clonally-derived rat liver epithelial cell lines that were transformed either by exposure to chemical carcinogen or stable transfection of activated Ha-ras. We found that steady-state levels of TGFalpha mRNA in both series of transformed lines were induced 25- to 50-fold over those in the respective normal parental cells. This induction, which occurred without amplification of the TGF alpha gene, was accompanied by at least a five- to 10-fold increase in transcription along the entire length of the gene with no evidence of a transcriptional attenuation or arrest mechanism in the normal cells. Analysis of the TGFalpha promoter and flanking regions did not support a correlation between the extent of methylation and the level of expression, but did reveal several DNase I hypersensitive sites spanning from -14 to +8 kilobases. Two of these sites were differentially observed in cells displaying high and low TGFalpha gene transcription, while a third site correlated with TPA-induced expression. Finally, measurement of TGFalpha mRNA decay in the presence of Actinomycin D revealed a consistent 1.5- to 3.2-fold increase in the half-life of the TGFalpha transcript in the various transformed cell lines. These results indicate that transformation-mediated induction of TGFalpha gene expression in rat liver epithelial cells occurs through both transcriptional and post-transcriptional mechanisms, but is primarily the result of TGFalpha promoter activation.

journal_name

Oncogene

journal_title

Oncogene

authors

Berkowitz EA,Hissong MA,Lee DC

subject

Has Abstract

pub_date

1996-05-02 00:00:00

pages

1991-2002

issue

9

eissn

0950-9232

issn

1476-5594

journal_volume

12

pub_type

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