Triiodothyronine utilizes phosphatidylinositol 3-kinase pathway to activate anti-apoptotic myeloid cell leukemia-1.
Triiodothyronine (T(3)) 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 T(3); 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 T(3) increases transcription from the MCL-1 promoter twofold in the presence of thyroid hormone receptor beta1, but not of its alpha1 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 T(3)-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 T(3), 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 T(3) regulates apoptosis.
Pietrzak
Maciej
M
Department of Endocrinology, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
Puzianowska-Kuznicka
Monika
M
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D020218:Response Elements; D047488:Retinoid X Receptors / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology*
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D014284:Triiodothyronine; D019869:Phosphatidylinositol 3-Kinases