A role for basic transcription element-binding protein 1 (BTEB1) in the autoinduction of thyroid hormone receptor β

Thyroid hormone (T-3) induces gene regulation programs necessary for tadpole metamorphosis. Among the earliest responses to T3 are the up-regulation of T3 receptor beta (TR beta; autoinduction) and BTEB1 (basic transcription element-binding protein 1). BTEB1 is a member of the Kruppel family of transcription factors that bind to GC-rich regions in gene promoters. The proximal promoter of the Xenopus laevis Tr beta A gene has seven GC-rich sequences, which led us to hypothesize that BTEB1 binds to and regulates Tr beta A. In tadpoles and the frog fibroblast-derived cell line XTC-2, T3 up-regulated Bteb1 mRNA with faster kinetics than Tr beta A, and Bteb1 mRNA correlated with increased BTEB1 protein expression. BTEB1 bound to GC-rich sequences in the proximal Tr beta A promoter in vitro. By using chromatin immunoprecipitation assay, we show that BTEB1 associates with the Tr beta A promoter in vivo in a T3 and developmental stage-dependent manner. Induced expression of BTEB1 in XTC-2 cells caused accelerated and enhanced autoinduction of the Tr beta A gene. This enhancement was lost in N-terminal truncated mutants of BTEB1. However, point mutations in the zinc fingers of BTEB1 that destroyed DNA binding did not alter the activity of the protein on Tr beta A autoinduction, suggesting that BTEB1 can function in this regard through protein-protein interactions. Our findings support the hypothesis that BTEB1 associates with the Tr beta A promoter in vivo and enhances autoinduction, but this action does not depend on its DNA binding activity. Cooperation among the protein products of immediate early genes may be a common mechanism for driving developmental signaling pathways.