AP-1 and T3RE cis elements operate as a functional unit in the transcriptional control of the human malic enzyme gene

The human malic enzyme (hME) promoter contains an inverted palindromic (IP4) 3,5,3'-triiodo-thyronine (T3) response element (T3RE) 15 bp downstream from an activating protein-1 (AP-1) site. The purpose of this study was to analyze the functional relationship between both cis-acting elements. The following observations indicate that these two elements operate as a functional unit in controlling the human ME gene: (1) Mutations within either the AP-1 or the T3RE sites inhibited basal as well as stimulated promoter activity. (2) Unliganded T3 receptors (TR beta) bind to the T3RE preferentially as homodimers and repress basal promoter activity. (3) The stimulation of the AP-1 driven promoter activity by TPA was perturbed by overexpression of TR beta. T3 failed to stimulate transcription above the basal levels in cells overexpressing either TR beta or TR beta/retinoid acid receptor (RXR), indicating that TR beta acts primarily as a transcriptional repressor in the context of the hME. Moreover, the finding of a repressive effect of TR beta without DNA binding suggests the existence of both DNA-dependent and independent mechanisms of TR beta-induced repression of transcription. (C) 1999 Elsevier Science B.V. All rights reserved.