Triiodothyronine utilizes phosphatidylinositol 3-kinase pathway to activate anti-apoptotic myeloid cell leukemia-1

Abstract

Triiodothyronine (T3) regulates apoptosis in cells according to their developmental stage, cell type, and pathophysiological state. The molecular mechanisms of this regulation, however, have been largely unknown. In this work, we show that the expression of the myeloid cell leukemia-1 (MCL-1) protein, an anti-apoptotic member of B-cell lymphoma-2 (BCL-2) family, increases in thyroid hormone receptor-expressing human kidney-2 (HK2) cells upon 6-h incubation in 100 nM T3; we also describe the molecular mechanisms leading to this phenomenon. Transcription regulation assays performed in human embryonic kidney (HEK) 293 cells show that 100 nM T3 increases transcription from the MCL-1 promoter twofold in the presence of thyroid hormone receptor β1, but not of its α1 isoform. However, this increase is not a result of direct activation via the thyroid hormone-response element, TRE-DR4, located at the −998 to −983 position in this promoter; furthermore, the presence of 9-cis-retinoic acid receptor is not required. The promoter's activation is abolished in the presence of phosphatidylinositol 3-kinase (PI3-K) inhibitor, wortmannin. The −295 to −107 promoter fragment contains all sequences involved in T3-dependent activation of the MCL-1 promoter, and cAMP-responsive element located at the −262 to −255 position is a major mediator in this process. Therefore, MCL-1 expression is activated by T3, which increases its promoter activity by a non-genomic mechanism using the PI3-K signal transduction pathway. We propose that this is another mechanism by which T3 regulates apoptosis.