Decreased T Cell Erk Pathway Signaling May Contribute to the Development of Lupus Through Effects on Dna Methylation and Gene Expression

Oelke, Kurt; Richardson, Bruce C.

doi:10.1080/08830180490452567

Cited by 36 publications

(30 citation statements)

References 56 publications

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“…Overexpression of these two DNMTs and associated aberrant gene methylation are commonly seen in human cancers (24 -27). Consistent with the data in the present study, MAP kinase pathway was previously reported to cause DNMT expression and associated methylation and silencing of certain genes, such as T lymphocyte genes in lupus (22) and the tumor-suppressor gene Par-4 in transformed epithelial cells (28). Thus, promoter methylation may be a common mechanism in mediating gene silencing induced by aberrant activation of the MAP kinase pathway.…”

Section: Discussionsupporting

confidence: 79%

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Suppression of BRAF/MEK/MAP Kinase Pathway Restores Expression of Iodide-Metabolizing Genes in Thyroid Cells Expressing the V600E BRAF Mutant

Liu

Hou

et al. 2007

Clinical Cancer Research

162

110

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Purpose: The V600E BRAF mutant plays an important role in the pathogenesis of papillary thyroid cancer (PTC) and is associated with loss of expression of thyroid iodide-metabolizing genes. This study was done to investigate the restorability of expression of these genes by suppressing the BRAF/extracellular signal-regulated kinase kinase (MEK)/mitogen-activated protein (MAP) kinase pathway in V600E BRAF^harboring thyroid cells and to explore the mechanisms involved. Experimental Design: We used inducible expression of V600E BRAF, small interfering RNA transfection, and MEK-specific inhibitor to alter the MAP kinase pathway activities and subsequently examined the changes in expression, promoter activities, and methylation status of thyroid genes. Results: MEK inhibitor U0126 or cessation of V600E BRAF expression in PCCL3 cells restored expression of thyroid genes silenced by induced expression ofV600E BRAF. U0126 also restored the expression of these genes inV600E BRAF^harboring PTC-derived NPA cells. Knockdown of BRAF by specific small interfering RNA restored expression of some of these genes in NPA cells. Luciferase reporter assay using thyroid-stimulating hormone receptor gene as a model showed that the promoter activity was modulated by the MAP kinase pathway. Promoter methylation in association with DNA methyltransferase expression played a role in gene silencing by MAP kinase pathway in NPA cells. Conclusions:We showed the restorability of expression of thyroid iodide-metabolizing genes silenced by V600E BRAF, and linked this process to gene methylation in PTC cells. The results provide clinical implications that therapeutic targeting at the BRAF/MEK/MAP kinase pathway may be a good approach in restoring thyroid gene expression for effective radioiodine therapy for BRAF mutation-harboring PTC.Papillary thyroid cancer (PTC) accounts for 80% of all thyroid cancers and is the most common endocrine malignancy, with a currently rapidly increasing incidence (1, 2). Following thyroidectomy, radioiodine ablation is the mainstay of medical treatment for PTC, but patients may fail it when the cancer has lost radioiodine avidity, a primary cause for thyroid cancerrelated morbidity and mortality (3,4). This radioiodine treatment takes advantage of the unique function of thyroid cells to uptake, concentrate, and organify iodide, a substrate normally used for synthesis of thyroid hormones. Several thyroid-specific protein molecules play a key role in this iodide-metabolizing process, including thyroid stimulating hormone receptor (TSHR), sodium iodide symporter (NIS), thyroglobulin (Tg), thyroperoxidase (TPO), and the thyroid gene transcription factors TTF-1 and Pax-8 (5). Loss of expression of the genes for these molecules is common in thyroid cancer and is a sufficient cause for the loss of radioiodine avidity and failure of radioiodine therapy in this cancer (6 -10). Thus, a novel approach leading to restoration of expression of these thyroid iodide-metabolizing genes would provide great hope for those pati...

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Section: Discussionsupporting

confidence: 79%

“…22). As gene methylation was involved in MAP kinase pathway -induced silencing of thyroid genes in NPA cells, we investigated whether alteration in DNMT expression could be a mechanism in these cells.…”

Section: Resultsmentioning

confidence: 99%

Suppression of BRAF/MEK/MAP Kinase Pathway Restores Expression of Iodide-Metabolizing Genes in Thyroid Cells Expressing the V600E BRAF Mutant

Liu

Hou

et al. 2007

Clinical Cancer Research

162

110

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show abstract

“…[54][55][56] This has encouraged new lines of investigation in common inflammatory diseases, such as rheumatoid arthritis 57,58 and SLE, [59][60][61] that are likely to result in novel therapeutic strategies. A single illustration may help to emphasize the potential importance of specific epigenetic changes within a cell.…”

Section: Epigenetics In Inflammatory Conditionsmentioning

confidence: 99%

An alternative approach to medical genetics based on modern evolutionary biology. Part 5: epigenetics and genomics

Ryan

2009

J R Soc Med

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“…Methylation of gene promoter region is one of the most common epigenetic mechanisms in silencing tumor suppressor genes, and over-expression of DNMTs in humans is associated with a variety of cancers (Rodenhiser and Mann 2006). Furthermore, decreased methyltransferase activity and hypo-methylated DNA have been associated with autoimmune diseases (Richardson 2003;Oelke and Richardson 2004), and changes in the histone acetylation in central nervous system has been linked to cognitive decline in a mouse model (Peleg, Sananbenesi et al 2010). Although various epigenetic mechanisms work in concert to produce long-term and stable regulation of gene expression, not much is known on how these processes are linked and how specific patterns of epigenetic modification are inherited.…”

Section: Epigenetic Regulation and Its Implication On Periodontal Dismentioning

confidence: 99%

Periodontal Disease and Gingival Innate Immunity – Who Has the Upper Hand?

Chung¹,

An²

2012

Periodontal Diseases - A Clinician's Guide

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Decreased T Cell Erk Pathway Signaling May Contribute to the Development of Lupus Through Effects on Dna Methylation and Gene Expression

Cited by 36 publications

References 56 publications

Suppression of BRAF/MEK/MAP Kinase Pathway Restores Expression of Iodide-Metabolizing Genes in Thyroid Cells Expressing the V600E BRAF Mutant

Suppression of BRAF/MEK/MAP Kinase Pathway Restores Expression of Iodide-Metabolizing Genes in Thyroid Cells Expressing the V600E BRAF Mutant

An alternative approach to medical genetics based on modern evolutionary biology. Part 5: epigenetics and genomics

Periodontal Disease and Gingival Innate Immunity – Who Has the Upper Hand?

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