Expanded Insights Into Mechanisms of Gene Expression and Disease Related Disruptions

Smith, Moyra; Flodman, Pamela

doi:10.3389/fmolb.2018.00101

Cited by 14 publications

(14 citation statements)

References 65 publications

(71 reference statements)

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“…Unfortunately, we understand that there are still many obstacles, such as technical, ethical, and legal problems, involved in making this vision come true 4 . In the case of genetic diseases caused by single-gene defects, we can design an alternative way to alleviate genetic defects with our increased understanding of gene expression and protein regulation 5 . Since the function of RUNX2 was first identified in 1997 6 , profound knowledge about the gene expression regulation, protein–protein interactions, and posttranslational modifications (PTMs) of RUNX2 has accumulated.…”

Section: Introductionmentioning

confidence: 99%

RUNX2-modifying enzymes: therapeutic targets for bone diseases

et al. 2020

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RUNX2 is a master transcription factor of osteoblast differentiation. RUNX2 expression in the bone and osteogenic front of a suture is crucial for cranial suture closure and membranous bone morphogenesis. In this manner, the regulation of RUNX2 is precisely controlled by multiple posttranslational modifications (PTMs) mediated by the stepwise recruitment of multiple enzymes. Genetic defects in RUNX2 itself or in its PTM regulatory pathways result in craniofacial malformations. Haploinsufficiency in RUNX2 causes cleidocranial dysplasia (CCD), which is characterized by open fontanelle and hypoplastic clavicles. In contrast, gain-of-function mutations in FGFRs, which are known upstream stimulating signals of RUNX2 activity, cause craniosynostosis (CS) characterized by premature suture obliteration. The identification of these PTM cascades could suggest suitable drug targets for RUNX2 regulation. In this review, we will focus on the mechanism of RUNX2 regulation mediated by PTMs, such as phosphorylation, prolyl isomerization, acetylation, and ubiquitination, and we will summarize the therapeutics associated with each PTM enzyme for the treatment of congenital cranial suture anomalies.

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Section: Introductionmentioning

confidence: 99%

RUNX2-modifying enzymes: therapeutic targets for bone diseases

et al. 2020

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“…These patterns of synchronization ultimately guide developmental pathways during embryogenesis. Although aberrations in posttranslational modifications are often associated with developmental diseases including tumorigenesis [ 4 , 5 , 6 , 7 , 8 ], posttranslational events can also be manipulated and/or targeted for positive clinical applications [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Nitric Oxide as a Potential Adjuvant Therapeutic for Neuroblastoma: Effects of NO on Murine N2a Cells

Gordon

Reynolds

Brown

2020

Veterinary Sciences

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Neuroblastoma, the most common extracranial solid tumor in children, accounts for 15% of all pediatric cancer deaths. Pharmaceutical applications of S-Nitrosylation, which, under normal conditions is involved with a host of epigenetic and embryological development pathways, have exhibited great potential for use as adjuvant therapeutics in the clinical management of cancer. Herein, an evaluation of the impact of nitric oxide (NO) as a potent anticancer agent on murine neuroblastoma cells is presented. Excitingly cell viability, colony formation, and non-carcinogenic cell analysis illustrate the significance and practicality of NO as a cytotoxic anticancer therapeutic. Resazurin, WST-8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt), and MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphyltetrazolium bromide) assays consistently displayed a moderate,~20-25% reduction in cell viability after exposure to 1 mM S-Nitrosoglutathione (GSNO). A colony formation assay demonstrated that treated cells no longer exhibited colony formation capacity. Identically GSNO-treated Adult Human Dermal Fibroblasts (HDFa) exhibited no decrease in viability, indicating potential discrimination between neoplastic and normal cells. Collectively, our findings indicate a potential application for NO as an adjuvant therapeutic in the clinical management of neuroblastoma. Vet. Sci. 2020, 7, 51 2 of 15 and intricacy of disease progression and response to treatment, the International Neuroblastoma Staging System (INSS) was developed to classify the extent of the disease and impact the treatment approach [13]. Three distinct stages comprise the INSS: low, intermediate, and high risk. Each risk group is comprised of definitions containing the stage(s), patient age, presence/absence of the MYCN gene, histology, and DNA ploidy. Currently, low risk tumors represent ≤25% of initial diagnoses, intermediate risk represent about~15% of initial diagnoses, and high risk tumors are the most commonly diagnosed, at ≥60% [11]. In patients with low risk disease, surgery and observation are the central therapeutic options that contribute to >90% survival [14,15]. Patients with intermediate risk disease typically receive a variety of sequential treatments including chemotherapy, surgery, and radiation therapy, if necessary. Survival rates in this group drop some but remain favorable at >80% [16,17]. High risk treatment protocols commence in an identical manner and additional treatments are frequently required, such as immunotherapy and bone marrow transplant. Despite the advances in treatments for low and intermediate risk disease, patients with high risk disease continue to face particularly poor prognosis, with~40% five-year overall survival rates [18,19]. Overall relapse rates are additionally overwhelming, at >60% [12]. In a similar fashion, treatments for recurrent low-risk and intermediate-risk disease are largely effective. However, recurrent high-risk neuroblastoma remains a significant challenge. Due to the a...

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“…Complex regulatory mechanisms govern the way in which genotype and environment together lead to distinctive patterns of gene expression in different tissues at different developmental stages 20 , 66 , 67 . Methods are now available to explore tissue-specific gene expression and environmental regulatory mechanisms in OCD.…”

Section: Variation In Gene Expressionmentioning

confidence: 99%

Cutting-edge genetics in obsessive-compulsive disorder

Saraiva¹,

Cappi²,

Simpson³

et al. 2020

Fac Rev

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This article reviews recent advances in the genetics of obsessive-compulsive disorder (OCD). We cover work on the following: genome-wide association studies, whole-exome sequencing studies, copy number variation studies, gene expression, polygenic risk scores, gene–environment interaction, experimental animal systems, human cell models, imaging genetics, pharmacogenetics, and studies of endophenotypes. Findings from this work underscore the notion that the genetic architecture of OCD is highly complex and shared with other neuropsychiatric disorders. Also, the latest evidence points to the participation of gene networks involved in synaptic transmission, neurodevelopment, and the immune and inflammatory systems in this disorder. We conclude by highlighting that further study of the genetic architecture of OCD, a great part of which remains to be elucidated, could benefit the development of diagnostic and therapeutic approaches based on the biological basis of the disorder. Studies to date revealed that OCD is not a simple homogeneous entity, but rather that the underlying biological pathways are variable and heterogenous. We can expect that translation from bench to bedside, through continuous effort and collaborative work, will ultimately transform our understanding of what causes OCD and thus how best to treat it.

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Expanded Insights Into Mechanisms of Gene Expression and Disease Related Disruptions

Cited by 14 publications

References 65 publications

RUNX2-modifying enzymes: therapeutic targets for bone diseases

RUNX2-modifying enzymes: therapeutic targets for bone diseases

Nitric Oxide as a Potential Adjuvant Therapeutic for Neuroblastoma: Effects of NO on Murine N2a Cells

Cutting-edge genetics in obsessive-compulsive disorder

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