TEThered to Runx: Novel binding partners for runx factors

Li, Xiaodong; Decker, Matthew

doi:10.1016/j.bcmd.2010.03.002

Cited by 27 publications

(25 citation statements)

References 33 publications

(57 reference statements)

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“…We recently reported that EWSR1 and EWS‐FLI interact with the Runt domains of Runx2 and Runx1 [Li et al, 2010]. To determine the region of EWS‐FLI that binds Runx2, GST pulldown assays were performed.…”

Section: Resultsmentioning

confidence: 99%

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The Ewing's sarcoma fusion protein, EWS‐FLI, binds Runx2 and blocks osteoblast differentiation

McGee‐Lawrence

Decker

2010

J of Cellular Biochemistry

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Ewing’s sarcomas are highly aggressive round cell tumors of bone and soft tissues that afflict children and young adults. The majority of these tumors harbor the t(11;22) translocation and express the fusion protein EWS-FLI. Modern molecular profiling experiments indicate that Ewing’s tumors originate from mesenchymal precursors in young individuals. EWS-FLI alters the morphology of mesenchymal cells and prevents lineage specification; however, the molecular mechanisms for differentiation arrest are unclear. We recently showed that EWS-FLI binds Runx2, a master regulator of osteoblast differentiation. In this report, we demonstrate that FLI sequences within EWS-FLI are responsible for interactions with Runx2. EWS-FLI blocks the expression of osteoblastic genes in a multipotent progenitor cell line that requires Runx2 to integrate bone morphogenic protein (Bmp)2 signaling while increasing proliferation and altering cell morphology. These results demonstrate that EWS-FLI blocks the ability of Runx2 to induce osteoblast specification of a mesenchymal progenitor cell. Disrupting interactions between Runx2 and EWS-FLI1 may promote differentiation of the tumor cell.

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Section: Resultsmentioning

confidence: 99%

“…Runx2 is highly expressed in osteosarcomas, which are tumors derived from cells of a mature osteoblast phenotype, and is also easily detected in tumors that metastasize to the skeleton. We recently showed that Runx2 and Runx1 associate with TET family members, EWSR1, EWS‐FLI, and FUS, but the nature of those interactions remained unresolved [Li et al, 2010].…”

mentioning

confidence: 99%

The Ewing's sarcoma fusion protein, EWS‐FLI, binds Runx2 and blocks osteoblast differentiation

McGee‐Lawrence

Decker

2010

J of Cellular Biochemistry

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“…It has been reported that Runx2 is a direct phosphorylation target for PKA (22); nevertheless, increases in Runx2 phosphorylation were not detected in either control or knockdown cells (data not shown). Previous studies have also indicated that the transcriptional activity of Runx2 can be modulated by binding to other nuclear proteins, including transcriptional coactivators, corepressors, and other transcription factors (23)(24)(25). As examples of the latter with relevance to osteogenesis, the Foxo1 protein was found to interact directly with Runx2, and Atf4 could indirectly associate with Runx2 in MC3T3-E1 cells to regulate osteocalcin gene expression (26 -29).…”

Section: Loss Of Prkar1a Suppressed Runx2-mediated Transcriptionmentioning

confidence: 92%

Knockdown of PRKAR1A, the Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells

Zhang

Manchanda

et al. 2014

Molecular Endocrinology

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PRKAR1A is the gene encoding the type 1A regulatory subunit of protein kinase A, and it is the cause of the inherited human tumor syndrome Carney complex. Data from our laboratory has demonstrated that Prkar1a loss causes tumors in multiple cell lineages, including neural crest cells and osteoblasts. We have proposed that one mechanism by which tumorigenesis occurs is through the failure of terminal differentiation. In the present study, we directly test the effects of Prkar1a reduction on osteogenic differentiation in mouse and human cells in vitro. We found that Prkar1a levels noticeably increased during osteoblastic differentiation, indicating a positive correlation between the expression of Prkar1a and osteogenic potential. To validate this hypothesis, we generated stable Prkar1a knockdown in both mouse and human cells. These cells displayed significantly suppressed bone nodule formation and decreased expression of osteoblast markers such as osteocalcin and osteopontin. These observations imply that the antiosteogenic effect of Prkar1a ablation is not species or cell line specific. Furthermore, because Runt-related transcription factor-2 (Runx2) is a key mediator of osteoblast differentiation, we reasoned that the function of this transcription factor may be inhibited by Prkar1a knockdown. Chromatin immunoprecipitation and luciferase assays demonstrated that Prkar1a ablation repressed DNA binding and function of Runx2 at its target genes. Additionally, we determined that this effect is likely due to reductions in the Runx2-cooperating transcription factors forkhead box O1 and activating transcription factor 4. Taken together, this study provides direct evidence that ablation of Prkar1a interferes with signaling pathways necessary for osteoblast differentiation.

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“…Recently, FUS was also shown to affect the transcription of RNA Pol III (Tan & Manley, 2010). Additionally, FUS affects gene expression by acting as co-regulator of several transcription factors, including nuclear hormone receptors (Powers et al, 1998), Spi-1/PU.1 (Hallier et al, 1998), NF-κB (Uranishi et al, 2001), and RUNX transcription factors (Li et al, 2010). The involvement of FUS in RNA splicing by binding splicing regulator or pre-mRNA was widely investigated as well (Sama et al, 2014).…”

Section: Tdp-43 and Fus: A Perspective Into Neurobiology And Nuclementioning

confidence: 99%

TDP-43/FUS in motor neuron disease: Complexity and challenges

Guerrero

Wang

Mitra

et al. 2016

Progress in Neurobiology

105

122

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Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

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TEThered to Runx: Novel binding partners for runx factors

Cited by 27 publications

References 33 publications

The Ewing's sarcoma fusion protein, EWS‐FLI, binds Runx2 and blocks osteoblast differentiation

The Ewing's sarcoma fusion protein, EWS‐FLI, binds Runx2 and blocks osteoblast differentiation

Knockdown of PRKAR1A, the Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells

TDP-43/FUS in motor neuron disease: Complexity and challenges

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