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An isoform of branched-chain aminotransferase is a novel co-repressor for thyroid hormone nuclear receptors

H M Lin1, M Kaneshige, L Zhao

  • 1Gene Regulation Section, Laboratory of Molecular Biology, NCI and Laboratory of Cell Biochemistry and Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-0851, USA.

The Journal of Biological Chemistry
|September 28, 2001
PubMed

Insights

A novel protein, P3, interacts with thyroid hormone receptors (TRs) independently of thyroid hormone (T3). This protein, a variant of branched-chain aminotransferase (BCATm), acts as a ligand-independent co-repressor, impacting TR transcriptional activity.

Area of Science:

  • Molecular Endocrinology
  • Cell Biology
  • Biochemistry

Background:

  • Thyroid hormone receptors (TRs) are crucial for gene regulation, with their function modulated by co-regulatory proteins.
  • Tissue-specific co-regulators dictate distinct gene expression patterns and thyroid hormone (T3) target gene regulation.
  • Human colon carcinoma RKO cells display significant T3-independent transcriptional activity, suggesting the presence of unique co-regulatory factors.

Purpose of the Study:

  • To identify co-regulatory proteins interacting with TRbeta1 in RKO cells.
  • To characterize the function and mechanism of a novel TR-interacting protein found in RKO cells.

Main Methods:

  • Yeast two-hybrid system using full-length TRbeta1 as bait to screen for interacting proteins in RKO cells.
  • Identification and characterization of a positive clone, P3, as a spliced variant of human mitochondria branched-chain aminotransferase (BCATm).
  • Analysis of P3's cellular localization, interaction with TRbeta1, effect on TR DNA binding, and modulation of TR transcriptional activity, including the role of histone deacetylase activity.

Main Results:

  • A novel 12-amino acid deleted spliced variant of BCATm, designated P3, was identified and found to be abundantly expressed in RKO cells.
  • P3 demonstrated dual localization in both mitochondria and the nucleus.
  • P3 physically interacted with TRbeta1 in a T3-independent manner, inhibiting TR binding to the thyroid hormone-responsive element and repressing both unliganded TR repressor activity and ligand-dependent TR activation.

Conclusions:

  • P3 represents a novel class of co-regulators for TRs.
  • P3 functions as a ligand-independent co-repressor of TR, influencing its transcriptional activity through mechanisms including inhibition of DNA binding and potential involvement of histone deacetylase activity.
  • The discovery of P3 provides new insights into the complex regulation of thyroid hormone signaling pathways.

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