Hypoxia and Hypoxia-Inducible Factor-1 Target Genes in Central Nervous System Radiation Injury

: Hypoxia-inducible factor-1 (HIF-1) is a heterodimer protein composed of an oxygen-regulated functional subunit, HIF-1α, and a structural subunit, HIF-1β, belonging to the basic helix-loop-helix family. Strict regulation of HIF-1 protein stability and subsequent transcriptional activity involves various molecular interactions and is primarily controlled by post-transcriptional modifications. Hypoxia, owing to impaired cerebral blood flow, has been implicated in a range of central nervous system (CNS) diseases by exerting a deleterious effect on brain function. As a master oxygen-sensitive transcription regulator, HIF-1 is responsible for upregulating a broad spectrum of target genes involved in glucose metabolism, angiogenesis, and erythropoiesis to generate the adaptive response to avoid or minimize hypoxic brain injury. However, prolonged, severe oxygen deprivation may directly contribute to the role-conversion of HIF-1, namely. From neuroprotection to the promotion of cell death. Currently, an increasing number of studies support the fact HIF-1 is involved in a variety of CNS-related diseases, such as intracranial atherosclerosis, stroke, and neurodegenerative diseases. This review article chiefly focuses on the effect of HIF-1 on the pathogenesis and mechanism of progression of numerous CNS-related disorders by mediating the expression of various downstream genes and extensive biological functional events. It presents robust evidence that HIF-1 may represent a potential therapeutic target for CNS-related diseases.

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Regulation of Cholesterol Homeostasis by the Liver X Receptors in the Central Nervous System

Molecular Endocrinology ◽

10.1210/mend.16.6.0835 ◽

2002 ◽

Vol 16 (6) ◽

pp. 1378-1385 ◽

Cited By ~ 78

Author(s):

Karl D. Whitney ◽

Michael A. Watson ◽

Jon L. Collins ◽

William G. Benson ◽

Tammy M. Stone ◽

...

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

Cholesterol Efflux ◽

Target Genes ◽

Cholesterol Homeostasis ◽

Neuronal Cultures ◽

Primary Neuronal Cultures ◽

The Central Nervous System ◽

Lxr Agonists

Abstract The nuclear oxysterol receptors liver X receptor-α [LXRα (NR1H3)] and LXRβ (NR1H2) coordinately regulate genes involved in cholesterol homeostasis. Although both LXR subtypes are expressed in the brain, their roles in this tissue remain largely unexplored. In this report, we show that LXR agonists have marked effects on gene expression in murine brain tissue both in vitro and in vivo. In primary astrocyte cultures, LXR agonists regulated several established LXR target genes, including ATP binding cassette transporter A1, and enhanced cholesterol efflux. In contrast, little or no effect on gene expression or cholesterol efflux was detected in primary neuronal cultures. Treatment of mice with a selective LXR agonist resulted in the induction of several LXR target genes related to cholesterol homeostasis in the cerebellum and hippocampus. These data provide the first evidence that the LXRs regulate cholesterol homeostasis in the central nervous system. Because dysregulation of cholesterol balance is implicated in central nervous system diseases such as Alzheimer’s and Niemann-Pick disease, pharmacological manipulation of the LXRs may prove beneficial in the treatment of these disorders.

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An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia

Nucleic Acids Research ◽

10.1093/nar/gkp425 ◽

2009 ◽

Vol 37 (14) ◽

pp. 4587-4602 ◽

Cited By ~ 267

Author(s):

Yair Benita ◽

Hirotoshi Kikuchi ◽

Andrew D. Smith ◽

Michael Q. Zhang ◽

Daniel C. Chung ◽

...

Keyword(s):

Target Genes ◽

Hypoxia Inducible Factor ◽

Integrative Genomics ◽

Hypoxia Inducible Factor 1 ◽

The Core

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Hypoxia-Inducible Factor-1 in Multiple Myeloma Progression.

Blood ◽

10.1182/blood.v114.22.1812.1812 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1812-1812

Author(s):

Roberto Ria ◽

Antonia Reale ◽

Simona Berardi ◽

Claudia Piccoli ◽

Giulia Di Pietro ◽

...

Keyword(s):

Multiple Myeloma ◽

Endothelial Cells ◽

Target Genes ◽

Plasma Cells ◽

Hypoxia Inducible Factor ◽

Immunofluorescent Staining ◽

Enzyme Linked Immunosorbent Assay ◽

Vegf Receptor ◽

Rt Pcr ◽

Hypoxia Inducible Factor 1

Abstract Abstract 1812 Poster Board I-838 Multiple Myeloma (MM) is a malignancy of immunoglobulin (Ig)-synthesizing plasma cells, that home to and expand in the bone marrow. Similarly to other tumours its development is correlated to the formation of regions of hypoxia, which may be a prognostic indicator and determinant of malignant progression. It is known how in solid tumours the degree of intra-tumoral hypoxia is positively correlated with the expression of the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 is composed of HIF-1á and HIF-1β subunits and its production has been identified as a key element in allowing cells to adapt and survive in a hostile hypoxic environment via a variety of pathways. In hypoxia conditions, the HIF-1á subunit becomes stable and regulates the expression of target genes. When activated HIF-1á also targets those genes which are required for angiogenesis, the development of new blood vessels from an existing vascular network. Angiogenesis represents a constant hallmark of MM progression. In response to hypoxia plasma cells and stromal cells (endothelial cells [ECs], macrophages, mast cells) within the tumour express Vascular Endothelial Growth Factor (VEGF), a mitogen and survival factor specific for endothelial cells. VEGF is the major regulator of tumor-associated angiogenesis. HIF-1á directly activates transcription of the VEGF gene and this leads to autocrine signal transduction that is critical for angiogenesis. In this study we demonstrate the role of HIF-1á in MM angiogenesis. The constitutive stabilization of HIF-1á contributes to increase angiogenesis in MM. Our data show that HIF-1á is stabilized in the nucleus of MM endothelial cells (MMECs) but not in ECs of Monoclonal Gammopathies of Undetermined Significance (MGECs) and in Human Umbilical Vein ECs (HUVECs) used as controls. Western Blot and Enzyme-Linked Immunosorbent Assay (ELISA) analyses show the overexpression of HIF-1á and the proteic products of its target genes VEGF and VEGF Receptor (VEGFR)-1, in patients with relapsed disease and in MM progression but not in patients with nonactive MM (avascular phase). Moreover, immunofluorescent staining confirm the nuclear stabilization of HIF-1á in MMECs. At mRNA level all ECs express same quantity of HIF-1á mRNA, as confirmed by RT-PCR and Real-time RT-PCR, indicating that in MMECs the post-trascriptional control is affected. Finally, we show that the inhibition of HIF-1á by siRNA suppresses vessel formation in vitro and promote ECs apoptosis. Our findings indicate that HIF-1á plays an important role in MM progression and that it is correlated to the angiogenic switch from nonactive MM to active MM. Furthermore these data suggest that HIF-1á may represent a target for the MM antiangiogenic treatment. Disclosures No relevant conflicts of interest to declare.

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