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Hypoxic regulation of ADAMTS-2 and -3 (a disintegrin and matrix metalloproteinase with thrombospondin motifs 2 and 3) procollagen N proteinases by HIF-1α in endothelial cells

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Abstract

ADAMTS-2 and ADAMTS-3, known as procollagen amino proteases (PNP), are primarily responsible for processing the amino ends of the fibrillar collagen precursors. ADAMTS-2 is a highly expressed gene in type I collagen-rich tissues, such as skin, bones, tendons, and aorta. ADAMTS-3 is mainly expressed in cartilage, where it colocalizes with type II procollagen and in the nervous system. Studies about ADAMTS-2 and ADAMTS-3 enzymes primarily focused on their collagen processing activity. Knowledge about the transcriptional regulations of these genes is rather limited. Here we analyzed the transcriptional regulations of ADAMTS-2 and ADAMTS-3 genes under chemically induced hypoxic conditions in endothelial cell model, HUVECs. We elucidated that hypoxia is the potent positive regulator of ADAMTS-2 and ADAMTS-3 genes. qRT-PCR and western blotting studies revealed that ADAMTS-2 and ADAMTS-3 expressions were increased at mRNA and protein levels under chemically induced hypoxic conditions in HUVECs. In addition, Transient transfection experiments of ADAMTS-2 and ADAMTS-3 promoter–reporter constructs indicated that low oxygen conditions increased ADAMTS-2 and ADAMTS-3 promoter activities. Furthermore, the DNA–protein interaction assay provided evidence of the functional binding of HIF-1α on bioinformatically determined HRE regions on the ADAMTS-2 and ADAMTS-3 promoters.

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Acknowledgements

Saos-2, MG-63, and HUVEC cells were from ATCC. Laboratories at Balıkesir University, Molecular Biology and Genetics Department were used for the experiments

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Authors and Affiliations

  1. Department of Stem Cell and Tissue Regeneration, Institute of Health Sciences, Kocaeli University, 4138, Kocaeli, Turkey

    Candan Altuntaş

  2. Department of Translational Oncology, Institute of Oncology, Dokuz Eylül University, İzmir, Turkey

    Meltem Alper

  3. Faculty of Science and Literature, Department of Molecular Biology, Balıkesir University, 10145, Balıkesir, Turkey

    Yasemin Keleş, Feyza Nur Sav & Feray Köçkar

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  1. Candan Altuntaş
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Contributions

All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by CA, MA, and FK. The first draft of the manuscript was written by CA, MA, and FK and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Feray Köçkar.

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Altuntaş, C., Alper, M., Keleş, Y. et al. Hypoxic regulation of ADAMTS-2 and -3 (a disintegrin and matrix metalloproteinase with thrombospondin motifs 2 and 3) procollagen N proteinases by HIF-1α in endothelial cells. Mol Cell Biochem 478, 1151–1160 (2023). https://doi.org/10.1007/s11010-022-04549-3

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