HIF1A Gene Transcription Is Dependent on a Core Promoter Sequence Encompassing Activating and Inhibiting Sequences Located Upstream from the Transcription Initiation Site and cis Elements Located within the 5′UTR

Minet, Emmanuel; Ernest, Isabelle; Michel, G.; Roland, Isabelle; Remacle, José; Raes, Martine; Michiels, Carine

doi:10.1006/bbrc.1999.0995

Cited by 111 publications

(105 citation statements)

References 16 publications

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“…As HIF-1a and HIF-2a mRNA expression was induced under hypoxia in HepG2 cells and the HIF1a promotor contains hypoxia-responsive elements, 17 we suggest that both isoforms regulate each other. Furthermore, HIF-1b expression was enhanced in perinecrotic areas of spheroids, presumably as a result of glucose deficiency, which accompanies hypoxia in spheroids and is known to induce HIF-1b expression.…”

Section: Discussionmentioning

confidence: 67%

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

et al. 2010

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Hypoxia-inducible factors (HIFs) provoke adaptation to hypoxic stress occurring in rapidly growing tumor tissues. Therefore, overexpression of HIF-1 or HIF-2 is a common feature in hepatocellular carcinoma but their specific function is still controversially discussed. To analyze HIF function in hypoxia-induced cell death we created a stable knockdown of HIF-1a and HIF-2a in HepG2 cells and generated tumor spheroids as an in vitro hepatocellular carcinoma model. Knockdown of HIF-1a enhanced expression of HIF-2a and vice versa. Unexpectedly, knockdown of HIF-1a or HIF-2a increased cell viability as well as spheroid size and decreased caspase-3 activity. Antiapoptotic Bcl-X L expression increased in both knockdown spheroids, whereas proapoptotic Bax was only reduced in HIF-1a-knockdown cells. Furthermore, an HIF-2a-knockdown significantly increased Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) expression in an HIF-1a-dependent manner. Concomitantly, electron microscopy revealed a substantial increase in autophagosomal structures in HIF-2a-knockdown spheroids and mito-/lysotracker costaining confirmed lysosomal activity of these autophagosomes. Blocking autophagosome maturation using 3-methyladenine restored cell death in HIF-2a-knockdown clones comparable to wildtype cells. Conclusion: An HIF-1a-knockdown increases HIF-2a expression and shifts the balance of Bcl-2 family members toward survival. The knockdown of HIF-2a raises autophagic activity and attenuates apoptosis by enhancing HIF-1a expression. Our data indicate that enhanced expression of one HIF-isoform causes a survival advantage in hepatocellular carcinoma development. (HEPATOLOGY 2010;51:2183-2192

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Section: Discussionmentioning

confidence: 67%

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

et al. 2010

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“…Whether expression of any of these genes is reduced in Sp1/Sp3 compound heterozygous embryos and might thus contribute to the observed phenotype remains to be established. For the Hif1 gene, it was shown that Hif1A gene transcription is dependent on Sp binding sites (Minet et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Sp1/Sp3 compound heterozygous mice are not viable: Impaired erythropoiesis and severe placental defects

Krüger

Vollmer

Simmons

et al. 2007

Developmental Dynamics

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“…In addition, it is involved in the active regulation of vascular endothelial growth factor (VEGF) which is another HIF-1α regulated hypoxia gene (34). Since the HIF-1α promoter contains SP1-specific transcription elements (35), SP1 may also be an important factor in NDRG1 regulation.…”

Section: Time-and Oxygen-dependent Expression and Regulation Of Ndrg1mentioning

confidence: 99%

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

et al. 2017

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Abstract. N-myc downstream-regulated gene 1 (NDRG1) is a tumor suppressor with the potential to suppress metastasis, invasion and migration of cancer cells. It is regulated under stress conditions such as starvation or hypoxia. NDRG1 regulation is both induced and controlled by HIF-1α-dependent and -independent pathways under hypoxic conditions. However, there are profound differences in the way NDRG1 expression is regulated by HIF-1α and other transcription factors. Therefore, we aimed to define the time-dependent pattern of NDRG1 mRNA and protein expression in human glioblastoma cell lines in extreme hypoxia and after re-oxygenation as well as under normoxic conditions. Furthermore, we ascribe the regulation of NDRG1 to the transcription factors HIF-1α, SP1, CEBPα, YB-1 and Smad7 in a time-dependent manner. The human malignant glioma cell lines U87-MG, U373 and GaMG were cultured for 1, 6 and 24 h under hypoxic (0.1% O 2 ) conditions and then they were re-oxygenated. The mRNA expression of NDRG1, HIF-1α SP1, CEBPα, YB-1 and Smad7 was measured using semi-quantitative RT-PCR analysis. Their protein expression was analyzed using western blotting. Our experiments revealed that long-term (24 h), but not short-term hypoxia led to the induction of NDRG1 expression in human glioma cell lines. NDRG1 expression was found to correlate with the protein expression of HIF-1α, SP1, CEBPα, YB-1 and Smad7. The present study suggests for the first time that SP1 regulates NDRG1 expression in glioma cells under hypoxia in a time-dependent manner along with HIF-1α, CEBPα, YB-1 and Smad7. These molecules, each separately or in combination, may possess the potential to become target molecules for antitumor therapeutic approaches particularly in human brain tumors.

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HIF1A Gene Transcription Is Dependent on a Core Promoter Sequence Encompassing Activating and Inhibiting Sequences Located Upstream from the Transcription Initiation Site and cis Elements Located within the 5′UTR

Cited by 111 publications

References 16 publications

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

Roles of Hypoxia-Inducible Factor-1α (Hif-1α) Versus Hif-2α in the Survival of Hepatocellular Tumor Spheroids

Sp1/Sp3 compound heterozygous mice are not viable: Impaired erythropoiesis and severe placental defects

Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells

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