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This Article Full Text Full Text (PDF) All Versions of this Article: JME-08-0010v1 41/3/177    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Pietrzak, M. Articles by Puzianowska-Kuznicka, M. Search for Related Content PubMed PubMed Citation Articles by Pietrzak, M. Articles by Puzianowska-Kuznicka, M.

¹ Department of Endocrinology, Medical Research Center, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland² Department of Biochemistry and Molecular Biology, Medical Center of Postgraduate Education, Marymoncka 99, 01-813 Warsaw, Poland

(Correspondence should be addressed to M Puzianowska-Kuznicka; Email: monika{at}amwaw.edu.pl)

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 1 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.