Calreticulin Enhances the Transcriptional Activity of Thyroid Transcription Factor-1 by Binding to Its Homeodomain

Lorena Perrone,Gianluca Tell,Roberto Di Lauro

doi:10.1074/jbc.274.8.4640

Abstract

Transcription factors are often regulated by associated protein cofactors that are able to modify their activity by several different mechanisms. In this study we show that calreticulin, a Ca2+-binding protein with chaperone activity, binds to thyroid transcription factor-1 (TTF-1), a homeodomain-containing protein implicated in the differentiation of lung and thyroid. The interaction between calreticulin and TTF-1 appears to have functional significance because it results in increased transcriptional stimulation of TTF-1-dependent promoters. Calreticulin binds to the TTF-1 homeodomain and promotes its folding, suggesting that the mechanism involved in stimulation of transcriptional activity is an increase of the steady-state concentration of active TTF-1 protein in the cell. We also demonstrate that calreticulin mRNA levels in thyroid cells are under strict control by the thyroid-stimulating hormone, thus implicating calreticulin in the modulation of thyroid gene expression by thyroid-stimulating hormone.

Highlights

Thyroid transcription factor-1 (TTF-1)1 is a homeodomaincontaining protein implicated in the transcriptional activation of genes expressed exclusively in thyroid [1, 2] and lung [3]
We show in the present paper that calreticulin binds to the homeodomain of TTF-1 and is capable of stimulating its refolding
We suggest that the ability of calreticulin to promote renaturing of the TTF-1 HD may be responsible for the observed stimulation by calreticulin of TTF-1 transcriptional activity in cotransfection experiments, perhaps by increasing the steady-state concentration of properly folded homeodomain

Summary

Introduction

Thyroid transcription factor-1 (TTF-1)1 is a homeodomaincontaining protein implicated in the transcriptional activation of genes expressed exclusively in thyroid [1, 2] and lung [3]. Overexpression of calreticulin in HeLa cells results in an increased activity of TTF-1, suggesting that the interaction between these two proteins may have functional significance.

Results

Conclusion