The Role of Hypoxia Inducible Factor 1  in Cobalt Chloride Induced Cell Death in Mouse Embryonic Fibroblasts

Apelin, a novel peptide with significant cardioactive properties, is upregulated by insulin in adipocytes. However, the mechanism by which insulin promotes apelin production is unknown. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor involved in the angiogenic and metabolic responses to tissue hypoxia, has been shown to be activated by insulin in various settings. We therefore hypothesized that HIF-1 regulates insulin-mediated apelin expression in adipocytes. 3T3-L1 cells were differentiated into adipocytes in culture. For experiments, serum-starved 3T3-L1 cells were exposed to insulin and/or a 1% O2 environment. Apelin expression was assessed using quantitative real-time PCR and ELISA. To directly assess the role of HIF-1 in apelin production, we differentiated mouse embryonic fibroblasts (MEFs) containing a targeted deletion of the HIF-1α gene into adipocytes and measured their response to insulin and hypoxia. Apelin expression in mature 3T3-L1 adipocytes was increased significantly by insulin and was attenuated by pharmacological inhibition of insulin signaling. Exposure of cells to either hypoxia or the chemical HIF activators cobalt chloride (CoCl2) and dimethyloxaloylglycine (DMOG) resulted in significant upregulation of apelin, consistent with a role for HIF in apelin induction. Moreover, hypoxia-, CoCl2-, DMOG-, and insulin-induced apelin expression were all attenuated in differentiated HIF-1α-deficient MEFs. In summary, in cultured 3T3-L1 adipocytes and differentiated MEFs, HIF-1 appears to be involved in hypoxia- and insulin-induced apelin expression.

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GW27-e0564 The role of Hypoxia-Inducible Factor 1-Alpha (HIF1-α) in maintaining the balance between survival and cell death during the course of myocardial infraction.

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2016.07.082 ◽

2016 ◽

Vol 68 (16) ◽

pp. C22

Author(s):

Angelos Tsipis ◽

Anna Maria Athanassiadou ◽

Emmanouil Petrou ◽

Dimitrios Miliopoulos ◽

Aggeliki Gkouziouta ◽

...

Keyword(s):

Cell Death ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Myocardial Infraction

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Transcriptional Coactivator Cited2 Induces Bmi1 and Mel18 and Controls Fibroblast Proliferation via Ink4a/ARF

Molecular and Cellular Biology ◽

10.1128/mcb.23.21.7658-7666.2003 ◽

2003 ◽

Vol 23 (21) ◽

pp. 7658-7666 ◽

Cited By ~ 58

Author(s):

Kamil R. Kranc ◽

Simon D. Bamforth ◽

José Bragança ◽

Chris Norbury ◽

Maarten van Lohuizen ◽

...

Keyword(s):

Cell Proliferation ◽

Hypoxia Inducible Factor ◽

Polycomb Group ◽

Growth Fraction ◽

Fibroblast Proliferation ◽

Transcriptional Coactivator ◽

Mouse Embryonic Fibroblasts ◽

Embryonic Fibroblasts ◽

Hypoxia Inducible Factor 1 ◽

Polycomb Group Genes

ABSTRACT Cited2 (CBP/p300 interacting transactivator with ED-rich tail 2) is required for embryonic development, coactivation of transcription factor AP-2, and inhibition of hypoxia-inducible factor 1 transactivation. Cited2 is induced by multiple growth factors and cytokines and oncogenically transforms cells. Here, we show that the proliferation of Cited2 −/− mouse embryonic fibroblasts ceases prematurely. This is associated with a reduction in growth fraction, senescent cellular morphology, and increased expression of the cell proliferation inhibitors p16INK4a, p19ARF, and p15INK4b. Deletion of INK4a/ARF (encoding p16INK4a and p19ARF) completely rescued the defective proliferation of Cited2−/− fibroblasts. However, the deletion of INK4a/ARF did not rescue the embryonic malformations observed in Cited2 −/− mice, indicating that INK4a/ARF-independent pathways are likely to be involved here. We found that Cited2 −/− fibroblasts had reduced expression of the polycomb-group genes Bmi1 and Mel18, which function as INK4a/ARF and Hox repressors. Complementation with CITED2-expressing retrovirus enhanced proliferation, induced Bmi1/Mel18 expression, and decreased INK4a/ARF expression. Bmi1- and Mel18-expressing retroviruses enhanced the proliferation of Cited2 −/− fibroblasts, indicating that they function downstream of Cited2. Our results provide genetic evidence that Cited2 controls the expression of INK4a/ARF and fibroblast proliferation, at least in part via the polycomb-group genes Bmi1 and Mel18.

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The Loss of HIF1αLeads to Increased Susceptibility to Cadmium-Chloride-Induced Toxicity in Mouse Embryonic Fibroblasts

Journal of Toxicology ◽

10.1155/2011/391074 ◽

2011 ◽

Vol 2011 ◽

pp. 1-14 ◽

Cited By ~ 1

Author(s):

Ajith Vengellur ◽

Elizabeth Grier ◽

John J. LaPres

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Protective Role ◽

Activity Levels ◽

Wild Type ◽

Mouse Embryonic Fibroblasts ◽

Embryonic Fibroblasts ◽

Cadmium Treatment ◽

Increased Susceptibility

Wild-type and HIF1α −/− MEF cells were used to determine the role of HIF1α in cadmium-induced toxicity. Cadmium treatment did not affect HIF1-mediated transcription but led to caspase activation and apoptotic cell death in wild-type and HIF1α −/− cells. Cadmium-induced cell death, however, was significantly higher in HIF1α −/− cells as compared to their wild-type counterparts. Increased cell death in the HIF1α −/− cells was correlated with lower metallothionein protein, elevated levels of reactive oxygen species, and decreased superoxide dismutase enzyme activity. The total and oxidized glutathione levels, and, correspondingly, lipid peroxidation levels were elevated in the null cells compared to wild-type cells, indicating increased antioxidant demand and greater oxidative stress. Overall, the results suggest that basal levels of HIF1α play a protective role against cadmium-induced cytotoxicity in mouse embryonic fibroblasts by maintaining metallothionein and antioxidant activity levels.

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The role of programmed cell death ligand-1/ programmed cell death-1 (PD-L1/PD-1) in HPV-induced cervical cancer and potential for their use in blockade therapy

Current Medicinal Chemistry ◽

10.2174/0929867327666200128105459 ◽

2020 ◽

Vol 27 ◽

Cited By ~ 1

Author(s):

Lifang Zhang ◽

Yu Zhao ◽

Quanmei Tu ◽

Xiangyang Xue ◽

Xueqiong Zhu ◽

...

Keyword(s):

Cervical Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Immune Escape ◽

Hypoxia Inducible Factor ◽

Hpv Infection ◽

Advanced Cervical Cancer ◽

Cervical Carcinogenesis ◽

Programmed Cell Death 1

Background: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. Methods: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. Results: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signaling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and MicroRNAs, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in immune escape of cervical cancer through inhibition of host immune response. creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PD-L1/PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. Conclusion: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body’s immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

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Critical Role of PDE4D in β2-Adrenoceptor-dependent cAMP Signaling in Mouse Embryonic Fibroblasts

Journal of Biological Chemistry ◽

10.1074/jbc.m803306200 ◽

2008 ◽

Vol 283 (33) ◽

pp. 22430-22442 ◽

Cited By ~ 36

Author(s):

Matthew D. Bruss ◽

Wito Richter ◽

Kathleen Horner ◽

S.-L. Catherine Jin ◽

Marco Conti

Keyword(s):

Critical Role ◽

Camp Signaling ◽

Mouse Embryonic Fibroblasts ◽

Embryonic Fibroblasts

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The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

Cellular and Molecular Neurobiology ◽

10.1007/s10571-016-0440-6 ◽

2016 ◽

Vol 37 (6) ◽

pp. 969-977 ◽

Cited By ~ 12

Author(s):

Osigbemhe Iyalomhe ◽

Sabina Swierczek ◽

Ngozi Enwerem ◽

Yuanxiu Chen ◽

Monica O. Adedeji ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1

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Role of hypoxia-inducible factor-1α in autophagic cell death in microglial cells induced by hypoxia

Molecular Medicine Reports ◽

10.3892/mmr.2017.6277 ◽

2017 ◽

Vol 15 (4) ◽

pp. 2097-2105 ◽

Cited By ~ 6

Author(s):

Xintao Wang ◽

Jun Ma ◽

Qiang Fu ◽

Lei Zhu ◽

Zhiling Zhang ◽

...

Keyword(s):

Cell Death ◽

Hypoxia Inducible Factor ◽

Autophagic Cell Death ◽

Microglial Cells ◽

Hypoxia Inducible Factor 1Α

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Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

Neurosurgical FOCUS ◽

10.3171/2014.9.focus14496 ◽

2014 ◽

Vol 37 (6) ◽

pp. E8 ◽

Cited By ~ 18

Author(s):

Matthew Womeldorff ◽

David Gillespie ◽

Randy L. Jensen

Keyword(s):

Cellular Response ◽

Treatment Options ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Poor Patient ◽

Growth Development ◽

The Relationship ◽

Insight Into ◽

Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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