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Modulation of TAT gene induction by glucocorticoids involves a neutralizing sequence

D A Jackson1, C D Collier, H Oshima

  • 1Steroid Hormones Section, NIDDK/LMCB, National Institutes of Health, Bethesda, MD 20892, USA. steroids@helix.nih.gov

The Journal of Steroid Biochemistry and Molecular Biology
|August 27, 1998
PubMed
Summary

Researchers discovered a third element, a neutralizing sequence, that restores glucocorticoid modulatory element (GME) activity in the TAT gene. This finding explains how GME functions alongside negative elements for gene induction in rat hepatoma cells.

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Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Hormone Action

Background:

  • The endogenous TAT gene induction in FuS-5 rat hepatoma cells involves the glucocorticoid response element (GRE).
  • Two additional elements, a glucocorticoid modulatory element (GME) and a negative element, were previously identified as influencing TAT gene regulation.
  • The interplay between the GME and the negative element, and how GME activity is ultimately expressed, remained unclear.

Purpose of the Study:

  • To identify the mechanism by which the glucocorticoid modulatory element (GME) exerts its function in the presence of a negative element within the TAT gene.
  • To elucidate the role of a potential third element in restoring GME activity and enabling glucocorticoid induction of the TAT gene.
  • To understand the cooperative interaction of multiple regulatory elements with GREs in steroid-regulated gene expression.

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Main Methods:

  • Reporter construct analysis to assess the function of the GME and negative elements.
  • Site-directed mutagenesis and deletion analysis to pinpoint the location of the neutralizing sequence.
  • Investigation of element spacing effects on gene activity.
  • Comparison of reporter gene activity with the intact endogenous TAT gene expression.

Main Results:

  • A third element, termed a "neutralizing" sequence, was identified and localized near the GREs, separate from the GREs themselves.
  • This neutralizing sequence restores the activity of the GME when it is otherwise inhibited by the negative element.
  • Element spacing was found to be critical for the activity of individual GME and negative elements.
  • The native spacing within the TAT gene, incorporating the GME, negative element, and neutralizing sequence, successfully reproduced the activity of the intact gene when combined with the GRE.

Conclusions:

  • A novel three-element system (GME, negative element, and neutralizing sequence) cooperates with GREs to regulate TAT gene induction by glucocorticoids in Fu5-5 cells.
  • This complex regulatory arrangement, involving an activator, a silencer, and a neutralizer, highlights sophisticated control mechanisms in gene expression.
  • While potentially novel for steroid-regulated genes, such multi-element cooperative groupings are observed in the transcriptional control of other genes.