Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhabdomyosarcoma (RMS) is the commonest soft-tissue sarcoma in childhood and is characterized by expression of myogenic proteins, including the transcription factors MyoD and myogenin. There are two main subgroups, embryonal RMS and alveolar RMS (ARMS). Most ARMS are associated with chromosomal translocations that have breakpoints in introns of either PAX3 or PAX7, and FOXO1A. These translocations create chimeric transcription factors termed PAX3/FOXO1A and PAX7/FOXO1A respectively. Upon ectopic PAX3/FOXO1A expression, together with other genetic manipulation in mice, both differentiating myoblasts and satellite cells (the resident stem cells of postnatal muscle) can give rise to tumours with ARMS characteristics. As PAX3 and PAX7 are part of transcriptional networks that regulate muscle stem cell function in utero and during early postnatal life, PAX3/FOXO1A and PAX7/FOXO1A may subvert normal PAX3 and PAX7 functions. Here we examined how PAX3/FOXO1A and PAX7/FOXO1A affect myogenesis in satellite cells. PAX3/FOXO1A or PAX7/FOXO1A inhibited myogenin expression and prevented terminal differentiation in murine satellite cells: the same effect as dominant-negative (DN) Pax3 or Pax7 constructs. The transcription of MyoD-target genes myogenin and muscle creatine kinase were suppressed by PAX3/FOXO1A or PAX7/FOXO1A in C2C12 myogenic cells again as seen with Pax3/7DN. PAX3/FOXO1A or PAX7/FOXO1A did not inhibit the transcriptional activity of MyoD by perturbing MyoD expression, localization, phosphorylation or interaction with E-proteins. Chromatin immunoprecipitation on the myogenin promoter showed that PAX3/FOXO1A or PAX7/FOXO1A did not prevent MyoD from binding. However, PAX3/FOXO1A or PAX7/FOXO1A reduced occupation of the myogenin promoter by RNA polymerase II and decreased acetylation of histone H4, but did not directly bind to the myogenin promoter. Together, these observations reveal that PAX3/FOXO1A and PAX7/FOXO1A act to prevent myogenic differentiation via suppression of the transcriptional activation of MyoD-target genes.
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PMID:Alveolar rhabdomyosarcoma-associated proteins PAX3/FOXO1A and PAX7/FOXO1A suppress the transcriptional activity of MyoD-target genes in muscle stem cells. 2271 Jul 12

The purpose of our study was to investigate the prevalence of the PAX3/7-FKHR fusion genes and quantify the IGF2 gene expression in rhabdomyosarcoma (RMS) samples. Soft tissue sarcomas account 5% of childhood cancers and 50% of them are RMS. Morphological evaluation of pediatric RMS has defined two histological subtypes, embryonal (ERMS) and alveolar (ARMS). Chromosomal analyses have demonstrated two translocations associated with ARMS, resulting in the PAX3/7-FKHR rearrangements. Reverse transcriptase-polymerase chain reaction (RT-PCR) is extremely useful in the diagnosis of ARMS positive for these rearrangements. Additionally, several studies have shown a significant involvement of IGF pathway in the pathogenesis of RMS. The presence of PAX3/7-FKHR gene fusions was studied in 25 RMS samples from patients attending the IOP-GRAACC/UNIFESP and three RMS cell lines by RT-PCR. IGF2 gene expression was quantified by qPCR and related with clinic pathological parameters. Of the 25 samples, nine (36%) were ARMS and 16 (64%) were ERMS. PAX3/7-FKHR gene fusions expression was detected in 56% of ARMS tumor samples. IGF2 overexpression was observed in 80% of samples and could indicate an important role of this pathway in RMS biology.
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PMID:Investigation of PAX3/7-FKHR fusion genes and IGF2 gene expression in rhabdomyosarcoma tumors. 2307 86

Mutations in the RNA-binding protein FUS (fused in sarcoma)/TLS have been shown to cause the neurodegenerative disease amyotrophic lateral sclerosis (ALS), but the normal role of FUS is incompletely understood. We found that FUS binds the C-terminal domain (CTD) of RNA polymerase II (RNAP2) and prevents inappropriate hyperphosphorylation of Ser2 in the RNAP2 CTD at thousands of human genes. The loss of FUS leads to RNAP2 accumulation at the transcription start site and a shift in mRNA isoform expression toward early polyadenylation sites. Thus, in addition to its role in alternative RNA splicing, FUS has a general function in orchestrating CTD phosphorylation during RNAP2 transcription.
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PMID:FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2. 2324 33

After mRNA biogenesis, several proteins interact with the messenger to ensure its proper export to the cytoplasm. Some of these proteins will bind RNA early on, at the onset of transcription by RNA polymerase II holoenzyme, while others will join later for downstream processing steps, such as poly-adenylation or splicing, or may direct mRNA ribonucleoprotein particle migration to the nucleopore. We recently discovered that Arabidopsis plant knockout for the protein MOS11 (MODIFIER OF SNC1, 11) partially suppresses autoimmune responses observed in the TNL-type [TIR/NBS/LRR (Toll-interleukin-like receptor/nucleotide-binding site/C-terminal leucine-rich repeat)] R gene gain-of-function variant snc1 (suppressor of npr1-1, constitutive 1). This suppression of resistance to pathogens appears to be caused by a decrease in nuclear mRNA export in mos11-1 snc1 plants. In humans, the putative ortholog of MOS11, CIP29 (29-kDa cytokine-induced protein), interacts with three proteins that are also involved in mRNA export: DDX39 (DEAD-box RNA helicase), TAF15 of the FUS family (FUSED IN SARCOMA), and ALY (ALWAYS EARLY), a protein implicated in mRNA export in mammalian systems. These proteins have received very little attention in plants. Here, we will discuss their particularities and role in mRNA export and biotic stress.
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PMID:mRNA export: threading the needle. 2352 40

We conducted genetic analysis of the fused in sarcoma gene (FUS) in Chinese Han patients with essential tremor (ET) in a case-control association study. One hundred eighty unrelated patients with ET were screened for mutations in the coding region and exon-intron boundaries of FUS. Reverse transcriptase polymerase chain reaction analysis was performed to evaluate if the c.1176G>A variant results in change of splice site. Two hundred seventy-three normal control subjects were also analyzed when DNA variants were identified in ET cohort. A novel missense mutation, c.1176G>A (p.M392I), in FUS was identified in a 62-year-old patient. Four known variants (c.52C>A, p.P18T; c.147C>A, p.G49G; c.291T>C, p.Y97Y; c.684C>T, p.G228G) were observed in the case-control study without statistically significant differences in genotype and allele distributions. Mutation(s) in FUS might be associated with a small subset of ET cases in the Chinese population.
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PMID:Genetic analysis of the fused in sarcoma gene in Chinese Han patients with essential tremor. 2358 60

A 63-year-old man was referred to our office with an enlarging left adrenal mass found on work-up for prostate cancer. Imaging performed over the course of 6 months demonstrated an increasing left adrenal mass from 2.8 to 3.6 cm. Functional testing of the adrenal lesion was performed. The adrenal mass was non-functional. Owing to the enlarging size, the patient underwent a laparoscopic left adrenalectomy without complication and was discharged home the following day. Gross pathological evaluation demonstrated a 3.2 cm, well-encapsulated, partially cystic mass. Histological evaluation demonstrated a small round blue cell tumour suspicious of sarcoma. Immunohistochemical testing revealed strong CD99 positivity consistent with Ewing family of tumours. Reverse transcriptase PCR demonstrated the presence of the Ewing sarcoma fusion transcript. The patient is currently enrolled in an ongoing research chemotherapy protocol at our institution using vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide.
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PMID:Ewing sarcoma of the adrenal gland: a rare entity. 2385 84

The low-complexity (LC) domains of the products of the fused in sarcoma (FUS), Ewings sarcoma (EWS), and TAF15 genes are translocated onto a variety of different DNA-binding domains and thereby assist in driving the formation of cancerous cells. In the context of the translocated fusion proteins, these LC sequences function as transcriptional activation domains. Here, we show that polymeric fibers formed from these LC domains directly bind the C-terminal domain (CTD) of RNA polymerase II in a manner reversible by phosphorylation of the iterated, heptad repeats of the CTD. Mutational analysis indicates that the degree of binding between the CTD and the LC domain polymers correlates with the strength of transcriptional activation. These studies offer a simple means of conceptualizing how RNA polymerase II is recruited to active genes in its unphosphorylated state and released for elongation following phosphorylation of the CTD.
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PMID:Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains. 2426 90

Clear cell sarcoma (CCS) of the tendons and aponeuroses is a rare soft tissue sarcoma that morphologically resembles cutaneous malignant melanoma but exhibits a distinct molecular profile. Gastrointestinal (GI) CCS is extremely rare. In this study, two cases of CCS were presented: (1) left thumb and (2) jejunum. Case 1 manifested the characteristic CCS morphology. Case 2 was morphologically unusual and difficult to diagnose. Immunohistochemically, the two cases of tumor cells were diffusely positive for S100, vimentin, NSE protein, focal expression of CgA, and CAM2.5 protein. In case 1, the tumor cells were diffusely positive for HMB45, focal expression of CD56, and melan A antigen. Reverse transcriptase-polymerase chain reaction (RT-PCR) results confirmed the presence of the EWS/ATF1 translocation (type 1) in the two cases. Then, we detected 19 hotspot oncogenes in the two cases. To the best of our knowledge, this study is the first to apply a high-throughput OncoCarta panel 1.0 and MassARRAY system to detect 238 known mutations in 19 hotspot oncogenes in soft tissue clear cell sarcoma. In this study, no mutations were observed in these hotspot oncogenes in the two cases.
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PMID:Absence of 19 known hotspot oncogenic mutations in soft tissue clear cell sarcoma: two cases report with review of the literature. 2519 4

More than half of all human genes produce prematurely terminated polyadenylated short mRNAs. However, the underlying mechanisms remain largely elusive. CLIP-seq (cross-linking immunoprecipitation [CLIP] combined with deep sequencing) of FUS (fused in sarcoma) in neuronal cells showed that FUS is frequently clustered around an alternative polyadenylation (APA) site of nascent RNA. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) of RNA polymerase II (RNAP II) demonstrated that FUS stalls RNAP II and prematurely terminates transcription. When an APA site is located upstream of an FUS cluster, FUS enhances polyadenylation by recruiting CPSF160 and up-regulates the alternative short transcript. In contrast, when an APA site is located downstream from an FUS cluster, polyadenylation is not activated, and the RNAP II-suppressing effect of FUS leads to down-regulation of the alternative short transcript. CAGE-seq (cap analysis of gene expression [CAGE] combined with deep sequencing) and PolyA-seq (a strand-specific and quantitative method for high-throughput sequencing of 3' ends of polyadenylated transcripts) revealed that position-specific regulation of mRNA lengths by FUS is operational in two-thirds of transcripts in neuronal cells, with enrichment in genes involved in synaptic activities.
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PMID:Position-specific binding of FUS to nascent RNA regulates mRNA length. 2599 89

Pre-mRNA splicing is coupled to transcription by RNA polymerase II (RNAP II). We previously showed that U1 small nuclear ribonucleoprotein (snRNP) associates with RNAP II, and both RNAP II and U1 snRNP are also the most abundant factors associated with the protein fused-in-sarcoma (FUS), which is mutated to cause the neurodegenerative disease amyotrophic lateral sclerosis. Here, we show that an antisense morpholino that base-pairs to the 5' end of U1 snRNA blocks splicing in the coupled system and completely disrupts the association between U1 snRNP and both FUS and RNAP II, but has no effect on the association between FUS and RNAP II. Conversely, we found that U1 snRNP does not interact with RNAP II in FUS knockdown extracts. Moreover, using these extracts, we found that FUS must be present during the transcription reaction in order for splicing to occur. Together, our data lead to a model that FUS functions in coupling transcription to splicing via mediating an interaction between RNAP II and U1 snRNP.
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PMID:FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP. 2612 92


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