Thyroid hormone induces erythropoietin gene expression through augmented accumulation of hypoxia-inducible factor-1

Abstract

. Thyroid hormone induces erythropoietin gene expression through augmented accumulation of hypoxiainducible factor-1. Am J Physiol Regul Integr Comp Physiol 287: R600 -R607, 2004. First published May 20, 2004 10.1152/ajpregu. 00115.2004.-Oxygen is of vital importance for the metabolism and function of all cells in the human body. Hypoxia, the reduction of oxygen supply, results in adaptationally appropriate alterations in gene expression through the activation of hypoxia-inducible factor 1 (HIF-1) to overcome any shortage of oxygen. Thyroid hormones are required for normal function of nearly all tissues, with major effects on oxygen consumption and metabolic rate. Thyroid hormones have been found to augment the oxygen capacity of the blood by increasing the production of erythropoietin (EPO) and to improve perfusion by vasodilation through the augmented expression of adrenomedullin (ADM). Because the hypoxic expression of both genes depends on HIF-1, we studied the influence of thyroid hormone on HIF-1 activation in the human hepatoma cell line HepG2 under normoxic and hypoxic conditions. We found that thyroid hormones increased HIF-1␣ protein accumulation by increasing HIF-1␣ protein synthesis rather than attenuating its proteasomal degradation. HIF-1␣ expression directly correlated with augmented HIF-1 DNA binding and transcriptional activity of luciferase reporter plasmids, whereas HIF-1␤ levels remained unaffected. Knocking down HIF-1␣ by short interfering RNA (siRNA) clearly demonstrated that thyroid hormoneinduced target gene expression required the presence of HIF-1. Although an increased association of the two known coactivators of HIF-1, p300 and SRC-1, was found, thyroid hormone did not affect the activity of the isolated COOH-terminal transactivating domain of HIF-1␣. Increased synthesis of HIF-1␣ may contribute to the adaptive response of increased oxygen demand under hyperthyroid conditions. hypoxic gene expression; oxygen sensing ERYTHROPOIETIN (EPO), a 30.4-kDa glycoprotein hormone, is the major physiological stimulator of red blood cell formation in mammals (18). The main EPO production sites are the kidney in adults and the liver in fetuses (6). EPO production is induced by hypoxia, a state when oxygen supply does not cover the demand of the tissue. EPO mRNA levels are induced 50-to 100-fold in vitro by physiologically relevant levels of hypoxia (9). In vivo under severe hypoxia, production of EPO can be increased up to 1,000-fold (18, 29).Oxygen-dependent EPO expression is regulated by hypoxiainducible factor 1 (HIF-1), a heterodimer of the O 2 -labile 120-kDa ␣-subunit, and the constitutive 91-to 94-kDa ␤-subunit (37). The cellular levels of HIF-1␣ are adjusted by the ubiquitin-proteasome-dependent degradation of HIF-1␣ under normoxic conditions, allowing to tightly couple the protein appearance to the ambient oxygen tension (31). At high PO 2 , HIF-1␣ is posttranslationally hydroxylated at proline residues 402 and 564 by O 2 -sensitive prolyl hydroxylases, termed PHD1, PHD2, and PHD3, which ...

The Proinflammatory Cytokine Interleukin 1β and Hypoxia Cooperatively Induce the Expression of Adrenomedullin in Ovarian Carcinoma Cells through Hypoxia Inducible Factor 1 Activation

“…Several growth factors have been found to increase translation of HIF-1a (43, 44) and we have reported that thyroid hormones stimulate HIF-1a protein synthesis in the human hepatoma cell line HepG2 (45). Recently, TNFa was found to increase HIF-1a by enhanced translation through the internal ribosomal entry site (46).…”

Temperature regulates hypoxia-inducible factor-1 (HIF-1) in a poikilothermic vertebrate, crucian carp (Carassius carassius)

“…A variety of growth factors, hormones and cytokines regulate HIF-1 in mammalian cells by enhancing transcription and translation of HIF-1␣ and by affecting on DNA binding of HIF-1 dimer (Richard et al, 2000;Page et al, 2002;Treins et al, 2002;Ma et al, 2004). Moreover, HIF-1 appears to be needed for basal transcriptional levels of its target genes (Stroka et al, 2001;Mason et al, 2004;Huang et al, 2004).…”

Ghrelin Decreases Angiogenesis, HIF-1α and VEGF Protein Levels in Chronic Hypoxia in Lung Tissue of Male Rats

“…10 Immunohistochemical detection of CD31 has been used extensively to quantify angiogenesis. 10,12 In addition to hypoxia, some of hormones are effective on the expression of HIF or VEGF, such as thyroid hormones, 13 growth hormone, 14 GnRH, 15,16 estrogen, 17 LH, IGF-1, TNF-alpha. 18 Ghrelin is a 28-amino acid peptide hormone that is found in the secretory granules of X/A-like cells in gastric mucosa.…”