scholarly journals Hypoxia-Inducible Factor-1 Transactivates Transforming Growth Factor-β3 in Trophoblast

Endocrinology ◽  
2004 ◽  
Vol 145 (9) ◽  
pp. 4113-4118 ◽  
Author(s):  
Hirotaka Nishi ◽  
Toshihide Nakada ◽  
Mitsuyasu Hokamura ◽  
Yumi Osakabe ◽  
Osamu Itokazu ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
First Trimester ◽  
Vital Role ◽  
Low Oxygen ◽  
Mobility Shift ◽  
Trophoblast Differentiation ◽  
Hypoxia Inducible Factor 1 ◽  
Electrophoretic Mobility Shift Assays

Abstract Hypoxia occurs during the development of placenta in the first trimester and is implicated in trophoblast differentiation. Intervillous blood flow increases after 10 wk of gestation and results in exposure of trophoblast cells to oxygen. Before this time, low oxygen appears to prevent trophoblast differentiation toward an invasive phenotype. The oxygen-regulated early events of trophoblast differentiation are mediated by TGF-β3. TGF-β3 plays a vital role in trophoblast differentiation, and its overexpression can be found in preeclamptic placenta. We sought to determine the mechanism of TGF-β3 expression through hypoxia-inducible factor (HIF)-1. We show that HIF-1α and TGF-β3 are overexpressed in preeclamptic placenta. Hypoxia not only transactivates the TGF-β3 promoter activity but also enhances endogenous TGF-β3 expression. Using the TGF-β3 promoter deletion mutants, we show that the region between −90 and −60, which contains a putative HIF-1 consensus motif, is crucial for HIF-1-mediated transactivation. Electrophoretic mobility shift assays show that HIF-1 binds to the oligonucleotide containing the HIF-1 motif. Also, introduction of an antisense oligonucleotide for HIF-1 diminishes TGF-β3 expression during hypoxia, indicating that the up-regulation of TGF-β3 by hypoxia is mediated through HIF-1. Our results provide evidence that regulation of TGF-β3 promoter activity by HIF-1 represents a mechanism for trophoblast differentiation during hypoxia.

Physiologically low oxygen concentrations determined in fetal skin regulate hypoxia‐inducible factor 1 and transforming growth factor β3

2002 ◽  
Vol 16 (3) ◽  
pp. 411-413 ◽  
Author(s):  
Annette Scheid ◽  
Roland H. Wenger ◽  
Leonhard Schäffer ◽  
Isabelle Camenisch ◽  
Oliver Distler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Hypoxia Inducible Factor ◽  
Fetal Skin ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Concentrations

scholarly journals Induction of Gastrin Expression in Gastrointestinal Cells by Hypoxia or Cobalt Is Independent of Hypoxia-Inducible Factor (HIF)

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3006-3016 ◽  
Author(s):  
Lin Xiao ◽  
Suzana Kovac ◽  
Mike Chang ◽  
Arthur Shulkes ◽  
Graham S. Baldwin ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Mutational Analysis ◽  
Hypoxia Inducible Factor ◽  
Regulatory Elements ◽  
Luciferase Reporter ◽  
Human Gastric Cancer ◽  
Low Oxygen ◽  
Ags Cells ◽  
Cholecystokinin Receptor ◽  
Hypoxia Inducible Factor 1

Gastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporter assay. Exposure to a low oxygen concentration (1%) increased gastrin mRNA concentrations in wild-type AGS cells (AGS) and in AGS cells overexpressing the gastrin receptor (AGS-cholecystokinin receptor 2) by 2.1 ± 0.4- and 4.1 ± 0.3-fold (P < 0.05), respectively. The hypoxia mimetic, cobalt chloride (300 μM), increased gastrin promoter activity in AGS cells by 2.4 ± 0.3-fold (P < 0.05), and in AGS-cholecystokinin receptor 2 cells by 4.0 ± 0.3-fold (P < 0.05), respectively. The observations that either deletion from the gastrin promoter of the putative binding sites for the transcription factor hypoxia-inducible factor 1 (HIF-1) or knockdown of either the HIF-1α or HIF-1β subunit did not affect gastrin promoter inducibility under hypoxia indicated that the hypoxic activation of the gastrin gene is likely HIF independent. Mutational analysis of previously identified Sp1 regulatory elements in the gastrin promoter also failed to abrogate the induction of promoter activity by hypoxia. The observations that hypoxia up-regulates the gastrin gene in AGS cells by HIF-independent mechanisms, and that this effect is enhanced by the presence of gastrin receptors, provide potential targets for gastrointestinal cancer therapy.

scholarly journals Trophoblast lineage specification, differentiation and their regulation by oxygen tension

2018 ◽  
Vol 236 (1) ◽  
pp. R43-R56 ◽  
Author(s):  
Ching-Wen Chang ◽  
Anna K Wakeland ◽  
Mana M Parast
Keyword(s):  
Oxygen Tension ◽  
First Trimester ◽  
Arterial Blood Flow ◽  
Extravillous Trophoblast ◽  
Low Oxygen ◽  
Epithelial Stem Cells ◽  
Placental Development ◽  
Trophoblast Differentiation ◽  
Arterial Blood ◽  
Low Oxygen Tension

Development of the early embryo takes place under low oxygen tension. Under such conditions, the embryo implants and the trophectoderm, the outer layer of blastocyst, proliferate, forming the cytotrophoblastic shell, the early placenta. The cytotrophoblasts (CTBs) are the so-called epithelial ‘stem cells’ of the placenta, which, depending on the signals they receive, can differentiate into either extravillous trophoblast (EVT) or syncytiotrophoblast (STB). EVTs anchor the placenta to the uterine wall and remodel maternal spiral arterioles in order to provide ample blood supply to the growing fetus. STBs arise through CTB fusion, secrete hormones necessary for pregnancy maintenance and form a barrier across which nutrient and gas exchange can take place. The bulk of EVT differentiation occurs during the first trimester, before the onset of maternal arterial blood flow into the intervillous space of the placenta, and thus under low oxygen tension. These conditions affect numerous signaling pathways, including those acting through hypoxia-inducible factor, the nutrient sensor mTOR and the endoplasmic reticulum stress-induced unfolded protein response pathway. These pathways are known to be involved in placental development and disease, and specific components have even been identified as directly involved in lineage-specific trophoblast differentiation. Nevertheless, much controversy surrounds the role of hypoxia in trophoblast differentiation, particularly with EVT. This review summarizes previous studies on this topic, with the intent of integrating these results and synthesizing conclusions that resolve some of the controversy, but then also pointing to remaining areas, which require further investigation.

scholarly journals Hypoxia-Inducible Factor 1 Mediates Upregulation of Telomerase (hTERT)

2004 ◽  
Vol 24 (13) ◽  
pp. 6076-6083 ◽  
Author(s):  
Hirotaka Nishi ◽  
Toshihide Nakada ◽  
Satoru Kyo ◽  
Masaki Inoue ◽  
Jerry W. Shay ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Hypoxia Inducible Factor ◽  
Major Complication ◽  
Cancer Therapeutics ◽  
First Trimester ◽  
Telomerase Activity ◽  
Htert Promoter ◽  
Htert Expression ◽  
Human Disorders

ABSTRACT Hypoxia occurs during the development of the placenta in the first trimester and correlates with both trophoblast differentiation and the induction of telomerase activity through hTERT expression. We sought to determine the mechanism of regulation of hTERT expression during hypoxia. We show that hypoxia-inducible factor 1α (HIF-1α) and hTERT expression in the human placenta decrease with gestational age and that these are overexpressed in preeclamptic placenta, a major complication of pregnancy. Hypoxia not only transactivates the hTERT promoter activity but also enhances endogenous hTERT expression. The hTERT promoter region between −165 and +51 contains two HIF-1 consensus motifs, and in vitro reporter assays show that these are essential for hTERT transactivation by HIF-1. Introduction of an antisense oligonucleotide for HIF-1 diminishes hTERT expression during hypoxia, indicating that upregulation of hTERT by hypoxia is directly mediated through HIF-1. Our results provide persuasive evidence that the regulation of hTERT promoter activity by HIF-1 represents a mechanism for trophoblast growth during hypoxia and suggests that this may be a generalized response to hypoxia in various human disorders including resistance to cancer therapeutics by upregulating telomerase.

scholarly journals Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFβ3

2000 ◽  
Vol 105 (5) ◽  
pp. 577-587 ◽  
Author(s):  
Isabella Caniggia ◽  
Homa Mostachfi ◽  
Jennifer Winter ◽  
Max Gassmann ◽  
Stephen J. Lye ◽  
...  
Keyword(s):  
Biological Effects ◽  
Hypoxia Inducible Factor ◽  
Trophoblast Differentiation ◽  
Human Trophoblast ◽  
Hypoxia Inducible Factor 1

scholarly journals Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1

2003 ◽  
Vol 370 (1) ◽  
pp. 149-157 ◽  
Author(s):  
Yang-Sook CHUN ◽  
Ju-Yeon HYUN ◽  
Yong-Geun KWAK ◽  
In-San KIM ◽  
Chan-Hyung KIM ◽  
...  
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Promoter Activity ◽  
Hypoxia Inducible Factor ◽  
Gene Promoter ◽  
Ventricular Myocardium ◽  
Dominant Negative ◽  
Hypoxia Inducible Factor 1 ◽  
Binding Sequence ◽  
Atrial Natriuretic

Atrial natriuretic peptide (ANP) is a cardiac peptide, the transcription of which is up-regulated in the ischaemic ventricle. However, the molecular mechanism of ANP induction is unclear. This study demonstrated that ANP mRNA expression in rat ventricular myocardium is induced in an early phase of ischaemia, preceded by hypoxia-inducible factor-1 (HIF-1) α expression. The ANP gene was also induced by hypoxia or HIF-1 inducers such as CoCl2 and desferrioxamine in H9c2 and neonatal cardiomyocytes. The 2307bp 5′-flanking region of the rat ANP gene was cloned and fused to the luciferase gene. Evidence of the promoter activity was only apparent in the myocytes and was induced by hypoxia and HIF-1 inducers. The overexpression of HIF-1α markedly enhanced ANP promoter activity, and a dominant-negative isoform completely suppressed it. We demonstrated that the promoter regions are essential for hypoxic ANP induction. One promoter region, containing the HIF-1-binding sequence, is regulated directly by HIF-1. The other region is also activated by HIF-1 despite having no HIF-1-binding sequence. These results suggest that HIF-1 enhances the transactivation of the ANP gene in hypoxic myocytes, implying that stimulation of the ANP promoter by HIF-1 may in fact be responsible for the induction of the ANP gene in ischaemic ventricular myocardium.

scholarly journals Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc

2021 ◽  
Vol 22 (10) ◽  
pp. 5281
Author(s):  
Jin-Woo Kim ◽  
Neunghan Jeon ◽  
Dong-Eun Shin ◽  
So-Young Lee ◽  
Myongwhan Kim ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Structural Changes ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1 ◽  
Metabolic Activities ◽  
Cartilaginous Endplate ◽  
Ivd Degeneration ◽  
Complex Joint

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration.

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