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Roles of RUNX in Hypoxia-Induced Responses and Angiogenesis

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RUNX Proteins in Development and Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 962))

Abstract

During the past two decades, Runt domain transcription factors (RUNX1, 2, and 3) have been investigated in regard to their function, structural elements, genetic variants, and roles in normal development and pathological conditions. The Runt family proteins are evolutionarily conserved from Drosophila to mammals, emphasizing their physiological importance. A hypoxic microenvironment caused by insufficient blood supply is frequently observed in developing organs, growing tumors, and tissues that become ischemic due to impairment or blockage of blood vessels. During embryonic development and tumor growth, hypoxia triggers a stress response that overcomes low-oxygen conditions by increasing erythropoiesis and angiogenesis and triggering metabolic changes. This review briefly introduces hypoxic conditions and cellular responses, as well as angiogenesis and its related signaling pathways, and then describes our current knowledge on the functions and molecular mechanisms of Runx family proteins in hypoxic responses, especially in angiogenesis.

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Abbreviations

VEGF:

vascular endothelial growth factor

HIF:

hypoxia-inducible factor

PTM:

post-translational modification

CBFβ:

core binding factor β

PHD:

prolyl hydroxylase

pVHL:

von Hippel Lindau

FIH:

factor inhibiting HIF

PI3K:

phosphatidylinositol 3-kinase

MAPK:

mitogen-activated protein kinase

PKB:

protein kinase B

mTOR:

mammalian target of rapamycin

ERK:

extracellular signal-regulated kinase

S6 K:

S6 kinase

eIF-4E:

eukaryotic translational initiation factor 4E

4E–BP1:

eIF-4E-binding protein

MNK:

MAP kinase interacting kinase

VPF:

vascular permeability factor

HRE:

hypoxia-responsive element

PlGF:

placental growth factor

VEGFR:

VEGF-receptor

EC:

endothelial cell

eNOS:

endothelial nitric oxide

FAK:

focal adhesion kinase

Ang:

angiopoietin

PECAM:

platelet-endothelial cell-adhesion molecule

bFGF:

basic fibroblast growth factor

GM-CSF:

granulocyte macrophage-colony stimulating factor

EPC:

endothelial progenitor cell

CAC:

circulating angiogenic cell

TIMP:

tissue inhibitor of metalloproteinase

IGFBP-3:

insulin-like growth factor-binding protein-3

AGM:

aorta-gonad mesonephros

HSC:

hematopoietic stem cell

HSPC:

hematopoietic stem and progenitor cell

AML:

acute myeloid leukemia

C/EBPα:

CCAAT/enhancer-binding protein α

DNMT:

DNA methyltransferases

ER:

endoplasmic reticulum

UPR:

unfolded protein response

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

HDAC:

histone deacetylase

ODDD:

oxygen-dependent degradation domain

HBME:

bone marrow endothelial cell

MMP:

matrix metalloproteinase

HMT:

histone methyltransferase

BRD:

bromodomain

MVD:

microvascular density

vWF:

von Willebrand factor

Dll4:

Delta-like 4

Egr-3:

early growth response-3

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Acknowledgments

This work was supported by NRF and KSEF grants funded by the Korean government (MSIP) (2012R1A4A1028835 and 2013R1A2A2A01068868).

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  1. National Basic Research Laboratory of Vascular Homeostasis Regulation, BK21 Plus KNU Multi-Omics based Creative Drug Research Team, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, 41566, South Korea

    Sun Hee Lee, Sarala Manandhar & You Mie Lee Ph.D.

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Editors and Affiliations

  1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Yoram Groner

  2. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Yoshiaki Ito

  3. Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA

    Paul Liu

  4. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom

    James C. Neil

  5. Department of Cell and Development Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Nancy A. Speck

  6. Mayo Clinic, Rochester, Minnesota, USA

    Andre van Wijnen

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Lee, S.H., Manandhar, S., Lee, Y.M. (2017). Roles of RUNX in Hypoxia-Induced Responses and Angiogenesis. In: Groner, Y., Ito, Y., Liu, P., Neil, J., Speck, N., van Wijnen, A. (eds) RUNX Proteins in Development and Cancer. Advances in Experimental Medicine and Biology, vol 962. Springer, Singapore. https://doi.org/10.1007/978-981-10-3233-2_27

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