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  1. Article ; Online: Clinical investigation of hypoxia-inducible factors: getting there.

    Semenza, Gregg L

    The Journal of clinical investigation

    2024  Volume 134, Issue 3

    MeSH term(s) Humans ; Basic Helix-Loop-Helix Transcription Factors ; Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors ; Hypoxia-Inducible Factor 1, alpha Subunit
    Language English
    Publishing date 2024-02-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI176253
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  2. Article ; Online: Targeting intratumoral hypoxia to enhance anti-tumor immunity.

    Semenza, Gregg L

    Seminars in cancer biology

    2023  Volume 96, Page(s) 5–10

    Abstract: Cancers express a large battery of genes by which they establish an immunosuppressive tumor microenvironment. Many of these genes are induced by intratumoral hypoxia through transcriptional activation mediated by hypoxia-inducible factors HIF-1 and HIF-2. ...

    Abstract Cancers express a large battery of genes by which they establish an immunosuppressive tumor microenvironment. Many of these genes are induced by intratumoral hypoxia through transcriptional activation mediated by hypoxia-inducible factors HIF-1 and HIF-2. This review summarizes several recent reports describing hypoxia-induced mechanisms of immune evasion in sarcoma and breast, colorectal, hepatocellular, prostate and uterine cancer. These studies point to several novel therapeutic approaches to improve anti-tumor immunity and increase responses to immunotherapy.
    MeSH term(s) Male ; Humans ; Neoplasms/genetics ; Neoplasms/therapy ; Hypoxia/genetics ; Tumor Microenvironment/genetics
    Language English
    Publishing date 2023-09-16
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1033980-2
    ISSN 1096-3650 ; 1044-579X
    ISSN (online) 1096-3650
    ISSN 1044-579X
    DOI 10.1016/j.semcancer.2023.09.002
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  3. Article ; Online: Mechanisms of Breast Cancer Stem Cell Specification and Self-Renewal Mediated by Hypoxia-Inducible Factor 1.

    Semenza, Gregg L

    Stem cells translational medicine

    2023  Volume 12, Issue 12, Page(s) 783–790

    Abstract: Many advanced human cancers contain regions of intratumoral hypoxia, with O2 gradients extending to anoxia. Hypoxia-inducible factors (HIFs) are activated in hypoxic cancer cells and drive metabolic reprogramming, vascularization, invasion, and ... ...

    Abstract Many advanced human cancers contain regions of intratumoral hypoxia, with O2 gradients extending to anoxia. Hypoxia-inducible factors (HIFs) are activated in hypoxic cancer cells and drive metabolic reprogramming, vascularization, invasion, and metastasis. Hypoxia induces breast cancer stem cell (BCSC) specification by inducing the expression and/or activity of the pluripotency factors KLF4, NANOG, OCT4, and SOX2. Recent studies have identified HIF-1-dependent expression of PLXNB3, NARF, and TERT in hypoxic breast cancer cells. PLXNB3 binds to and activates the MET receptor tyrosine kinase, leading to activation of the SRC non-receptor tyrosine kinase and subsequently focal adhesion kinase, which promotes cancer cell migration and invasion. PLXNB3-MET-SRC signaling also activates STAT3, a transcription factor that mediates increased NANOG gene expression. Hypoxia-induced NARF binds to OCT4 and serves as a coactivator by stabilizing OCT4 binding to the KLF4, NANOG, and SOX2 genes and by stabilizing the interaction of OCT4 with KDM6A, a histone demethylase that erases repressive trimethylation of histone H3 at lysine 27, thereby increasing KLF4, NANOG, and SOX2 gene expression. In addition to increasing pluripotency factor expression by these mechanisms, HIF-1 directly activates expression of the TERT gene encoding telomerase, the enzyme required for maintenance of telomeres, which is required for the unlimited self-renewal of BCSCs. HIF-1 binds to the TERT gene and recruits NANOG, which serves as a coactivator by promoting the subsequent recruitment of USP9X, a deubiquitinase that inhibits HIF-1α degradation, and p300, a histone acetyltransferase that mediates acetylation of H3K27, which is required for transcriptional activation.
    MeSH term(s) Humans ; Female ; Hypoxia-Inducible Factor 1/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Hypoxia/metabolism ; Gene Expression Regulation, Neoplastic ; Neoplastic Stem Cells/metabolism ; Ubiquitin Thiolesterase/metabolism
    Chemical Substances Hypoxia-Inducible Factor 1 ; USP9X protein, human ; Ubiquitin Thiolesterase (EC 3.4.19.12)
    Language English
    Publishing date 2023-09-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 2642270-0
    ISSN 2157-6580 ; 2157-6580
    ISSN (online) 2157-6580
    ISSN 2157-6580
    DOI 10.1093/stcltm/szad061
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  4. Article ; Online: Regulation of Erythropoiesis by the Hypoxia-Inducible Factor Pathway: Effects of Genetic and Pharmacological Perturbations.

    Semenza, Gregg L

    Annual review of medicine

    2022  Volume 74, Page(s) 307–319

    Abstract: Red blood cells transport ... ...

    Abstract Red blood cells transport O
    MeSH term(s) Humans ; Erythropoiesis/genetics ; Prolyl-Hydroxylase Inhibitors/pharmacology ; Prolyl-Hydroxylase Inhibitors/therapeutic use ; Ketoglutaric Acids ; Hypoxia ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism
    Chemical Substances Prolyl-Hydroxylase Inhibitors ; Ketoglutaric Acids ; Basic Helix-Loop-Helix Transcription Factors
    Language English
    Publishing date 2022-06-30
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 207930-6
    ISSN 1545-326X ; 0066-4219
    ISSN (online) 1545-326X
    ISSN 0066-4219
    DOI 10.1146/annurev-med-042921-102602
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  5. Article ; Online: Hypoxia-inducible factors: roles in cardiovascular disease progression, prevention, and treatment.

    Semenza, Gregg L

    Cardiovascular research

    2022  Volume 119, Issue 2, Page(s) 371–380

    Abstract: Hypoxia-inducible factors (HIF)-1 and HIF-2 are master regulators of oxygen homeostasis that regulate the expression of thousands of genes in order to match O2 supply and demand. A large body of experimental data links HIF activity to protection against ... ...

    Abstract Hypoxia-inducible factors (HIF)-1 and HIF-2 are master regulators of oxygen homeostasis that regulate the expression of thousands of genes in order to match O2 supply and demand. A large body of experimental data links HIF activity to protection against multiple disorders affecting the cardiovascular system: ischemic cardiovascular disease (including coronary artery disease and peripheral artery disease), through collateral blood vessel formation and preconditioning phenomena; emphysema; lymphedema; and lung transplant rejection. In these disorders, strategies to increase the expression of one or both HIFs may be of therapeutic utility. Conversely, extensive data link HIFs to the pathogenesis of pulmonary arterial hypertension and drugs that inhibit one or both HIFs may be useful in treating this disease.
    MeSH term(s) Humans ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/prevention & control ; Coronary Artery Disease ; Cardiovascular System ; Hypoxia/metabolism ; Lung/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit
    Chemical Substances Hypoxia-Inducible Factor 1, alpha Subunit
    Language English
    Publishing date 2022-06-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80340-6
    ISSN 1755-3245 ; 0008-6363
    ISSN (online) 1755-3245
    ISSN 0008-6363
    DOI 10.1093/cvr/cvac089
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  6. Article ; Online: On either side of homeostasis:

    Prchal, Josef T / Semenza, Gregg L

    Haematologica

    2023  Volume 108, Issue 10, Page(s) 2564–2565

    MeSH term(s) Humans ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Mutation ; Homeostasis
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors
    Language English
    Publishing date 2023-10-01
    Publishing country Italy
    Document type Editorial ; Comment
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2023.283285
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  7. Article ; Online: Heritable disorders of oxygen sensing.

    Semenza, Gregg L

    American journal of medical genetics. Part A

    2021  Volume 185, Issue 11, Page(s) 3334–3339

    Abstract: Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced ... ...

    Abstract Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O
    MeSH term(s) Aryl Hydrocarbon Receptor Nuclear Translocator/genetics ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/metabolism ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Mutation/genetics ; Oxygen/metabolism ; Polycythemia/congenital ; Polycythemia/genetics ; Polycythemia/metabolism ; Polycythemia/pathology ; von Hippel-Lindau Disease/genetics ; von Hippel-Lindau Disease/metabolism ; von Hippel-Lindau Disease/pathology
    Chemical Substances ARNT protein, human ; Basic Helix-Loop-Helix Transcription Factors ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Aryl Hydrocarbon Receptor Nuclear Translocator (138391-32-9) ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2021-10-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.62521
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  8. Article ; Online: Heritable disorders of oxygen sensing.

    Semenza, Gregg L

    American journal of medical genetics. Part A

    2021  Volume 185, Issue 8, Page(s) 2576–2581

    Abstract: Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced ... ...

    Abstract Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O
    MeSH term(s) Biomarkers ; Diagnosis, Differential ; Genetic Association Studies ; Genetic Diseases, Inborn/diagnosis ; Genetic Diseases, Inborn/genetics ; Genetic Diseases, Inborn/metabolism ; Genetic Predisposition to Disease ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Oxygen/metabolism ; Phenotype ; Polycythemia/congenital ; Polycythemia/diagnosis ; Polycythemia/metabolism ; Signal Transduction ; von Hippel-Lindau Disease/diagnosis ; von Hippel-Lindau Disease/genetics ; von Hippel-Lindau Disease/metabolism
    Chemical Substances Biomarkers ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Oxygen (S88TT14065)
    Language English
    Publishing date 2021-05-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2108614-X
    ISSN 1552-4833 ; 0148-7299 ; 1552-4825
    ISSN (online) 1552-4833
    ISSN 0148-7299 ; 1552-4825
    DOI 10.1002/ajmg.a.62250
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  9. Article ; Online: Breakthrough science: hypoxia-inducible factors, oxygen sensing, and disorders of hematopoiesis.

    Semenza, Gregg L

    Blood

    2021  Volume 139, Issue 16, Page(s) 2441–2449

    Abstract: Hypoxia-inducible factors (HIFs) were discovered as activators of erythropoietin gene transcription in response to reduced oxygen (O2) availability. O2-dependent hydroxylation of HIFs on proline and asparagine residues regulates protein stability and ... ...

    Abstract Hypoxia-inducible factors (HIFs) were discovered as activators of erythropoietin gene transcription in response to reduced oxygen (O2) availability. O2-dependent hydroxylation of HIFs on proline and asparagine residues regulates protein stability and transcriptional activity, respectively. Mutations in genes encoding components of the O2-sensing pathway cause familial erythrocytosis. Several small-molecule inhibitors of HIF prolyl hydroxylases are currently in clinical trials as erythropoiesis-stimulating agents. HIFs are overexpressed in bone marrow neoplasms, and the development of HIF inhibitors may improve outcomes in these disorders.
    MeSH term(s) Hematopoiesis ; Humans ; Hypoxia/genetics ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/genetics ; Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism ; Oxygen/metabolism ; Polycythemia/genetics ; Polycythemia/metabolism
    Chemical Substances Hypoxia-Inducible Factor 1, alpha Subunit ; Hypoxia-Inducible Factor-Proline Dioxygenases (EC 1.14.11.29) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2021-08-18
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2021011043
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  10. Article ; Online: Intratumoral Hypoxia and Mechanisms of Immune Evasion Mediated by Hypoxia-Inducible Factors.

    Semenza, Gregg L

    Physiology (Bethesda, Md.)

    2021  Volume 36, Issue 2, Page(s) 73–83

    Abstract: Activation of the innate and adaptive immune systems represents a promising strategy for defeating cancer. However, during tumor progression, cancer cells battle to shift the balance from immune activation to immunosuppression. Critical sites of this ... ...

    Abstract Activation of the innate and adaptive immune systems represents a promising strategy for defeating cancer. However, during tumor progression, cancer cells battle to shift the balance from immune activation to immunosuppression. Critical sites of this battle are regions of intratumoral hypoxia, and a major driving force for immunosuppression is the activity of hypoxia-inducible factors, which regulate the transcription of large batteries of genes in both cancer and stromal cells that block the infiltration and activity of cytotoxic T lymphocytes and natural killer cells, while stimulating the infiltration and activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Targeting hypoxia-inducible factors or their target gene products may restore anticancer immunity and improve the response to immunotherapies.
    MeSH term(s) Basic Helix-Loop-Helix Transcription Factors ; Humans ; Hypoxia ; Immune Evasion ; Neoplasms
    Chemical Substances Basic Helix-Loop-Helix Transcription Factors
    Language English
    Publishing date 2021-02-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2158667-6
    ISSN 1548-9221 ; 1548-9213
    ISSN (online) 1548-9221
    ISSN 1548-9213
    DOI 10.1152/physiol.00034.2020
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