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RUNX2 Transcriptional Regulation in Development and Disease

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Nuclear Signaling Pathways and Targeting Transcription in Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

RUNX2, a member of the Runt family of transcription factors, plays important roles in embryonic development to promote osteogenesis and angiogenesis. RUNX2 has been implicated in the promotion of disease, including cleidocranial dysplasia, in cancer progression, and in metastasis of breast and prostate tumors. Its aberrant expression in disease states may be the result of several mechanisms such as haploinsufficiency, mutation, or amplification. In osteogenesis and cancer progression, interactions with core-binding factor-β (Cbf-β) and other cofactors are responsible for the regulation of target gene expression including, but not limited to, VEGF, osteopontin, osteocalcin, MMPs, and BMPs. RUNX2 transcriptional function within cells is regulated by signal transduction events leading to activation of ERK, Smads, cdks, and Akt, which result in phosphorylation, DNA binding, and transcriptional activation or repression of target genes. Constitutive activation of signaling pathways in tumor cells results in aberrant expression and activation of RUNX2. Specific RUNX2 targeting agents, therefore, may bypass the effects of redundant signal transduction pathways within cancer cells and be an effective therapeutic strategy for treatment of RUNX2-positive cancer patients.

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Abbreviations

1,25-OH D3:

1,25-OH Vitamin D3

AA:

Amino acid

Akt:

v-akt murine thymomaviral oncogene homolog 1 (aka: protein kinase B or PKB)

AML:

Acute myeloid leukemia

AR:

Aldose reductase (Context dependent. Not to be confused with androgen receptor)

AR:

Androgen receptor (Context dependent. Not to be confused with aldose reductase)

Atf6:

Activating transcription factor 6

BMP:

Bone morphogenetic protein

BMP-2:

Bone morphogenetic protein-2

BR-DIM:

3,3′-diindolylmethane

BSP:

Bone sialoprotein (aka: OPN)

C/EBPβ:

CCAAT/enhancer binding protein beta

CBFα:

Core-binding factor alpha

Cbf-β:

Core-binding factor subunit beta

Cbfβ-SMMHC:

Core binding factor β – smooth muscle myosin heavy chain

CBP:

CREB-binding protein

CCD:

Cleidocranial dysplasia

Cdk:

Cyclin-dependent kinase

CML:

Chronic myeloid leukemia

c-myc:

v-myc avian myelocytomatosis viral oncogene homolog

CoAA:

Co-activator activator

CSC:

Cancer stem cell

CSF2:

Colony stimulating factor 2

CST7:

Cystatin-7 (aka: cystatin-F or leukocystatin)

CTGF:

Connective tissue growth factor

Cx43:

Connexin 43

D-ELISA:

Deoxyribonucleic acid binding-enzyme-linked immunosorbent assay

DNA:

Deoxyribonucleic acid

EC:

Endothelial cell

EMT:

Epithelial mesenchymal transition

ERK:

Extracellular signal-regulated kinase

ERα:

Estrogen receptor alpha

EWS-FLI:

Ewing’s sarcoma breakpoint region 1 t(1122)(q24q12)

FGF2:

Fibroblast growth factor 2 (basic)

FGF2R:

Fibroblast growth factor 2 receptor

FoxO1:

Forkhead box O1

G9a:

Histone-lysine N-methyltransferase H3 lysine 9 specific 3 (aka: euchromatic histone-lysine N-methyltransferase)

GPCR:

G-protein coupled receptor

HBME:

Human bone marrow endothelial cell

HDAC:

Histone deacetylase

HG:

Hyperglycemia

HIF1-α:

Hypoxia inducible factor 1 alpha subunit

HUVEC:

Human umbilical vein endothelial cell

IGF-1:

Insulin-like growth factor-1

IGF-1R:

Insulin-like growth factor 1 receptor

Ihh:

Indian hedgehog

IL8:

Interleukin 8

JNK:

c-jun-N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MET:

Mesenchymal epithelial transition

miRNA:

Micro-ribonucleic acid

MLK3:

MAP3K mixed-lineage kinase 3

MM:

Multiple myeloma

MMP:

Matrix metalloproteinase

MORF:

Monocyte leukemia zinc finger related factor

MOZ:

Monocyte leukemia zinc finger protein

mRNA:

Messenger ribonucleic acid

mSin3a:

Mammalian transcriptional corepressors Sin3a

NBIF:

Neobavaisoflavone

NLS:

Nuclear localization signal

NMTS:

Nuclear matrix targeting signal

OPN:

Osteopontin (aka: BSP)

p21CIP1 :

Cyclin-dependent kinase inhibitor 1A

p27:

Cyclin-dependent kinase inhibitor 1B

p300:

E1A binding protein p300

p38:

p38 mitogen activated protein kinase

PEBP2α:

Polyomavirus enhancer-binding protein 2 alpha

PI3K:

Phosphoinositide-3-kinase

PIP:

Prolactin-induced protein

PKC:

Protein kinase C

PlxnA2:

Plexin A2

PSA:

Prostate specific antigen

PTEN:

Phosphatase and tensin homolog

PTHrP:

Parathyroid hormone-related protein

RANKL:

Receptor activator of nuclear factor kappa-B ligand

RNA:

Ribonucleic acid

Rorβ:

Retinoid-related orphan receptor beta

rRNA:

Ribosomal ribonucleic acid

RUNX1/2/3:

Runt-related transcription factor 1/2/3

SDC2:

Syndecan 2

SDF1:

Stromal cell-derived factor 1

SH3PXD2A:

SH3 and PX domain-containing protein 2A

shRNA:

Small hairpin ribonucleic acid

siRNA:

Small interfering ribonucleic acid

Smad:

Sma and mad related proteins

Smurf:

Smad specific E3 ubiquitin protein ligase

SNAI2:

Snail homolog 2/slug

SNP:

Single nucleotide polymorphism

Sox9:

Sex determining region Y-box 9 transcription factor

Suv39h1:

Suppressor of variegation 3–9 homolog 1

TAZ:

Transcriptional coactivator with a PDZ-binding motif

TGF-β:

Transforming growth factor beta

TLE-1:

Transducin-like enhancer protein 1

TLE2/3:

Transducin-like enhancer protein 2/3

UV:

Ultraviolet

VDR:

Vitamin D receptor

VEGF:

Vascular endothelial growth factor

Wip1:

Protein phosphatase magnesium-dependent 1 delta

WWOX:

WW domain containing oxidoreductase

WWP1:

WW domaincontaining E3 ubiquitin protein ligase 1

YAP:

Yes-associated protein

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  1. Department of Pathology, University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, USA

    Jessica L. Brusgard Ph.D. Student & Antonino Passaniti Ph.D.

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  2. Antonino Passaniti Ph.D.
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    Rakesh Kumar

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Brusgard, J.L., Passaniti, A. (2014). RUNX2 Transcriptional Regulation in Development and Disease. In: Kumar, R. (eds) Nuclear Signaling Pathways and Targeting Transcription in Cancer. Cancer Drug Discovery and Development. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-8039-6_3

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