Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In herpes simplex virus (HSV)-infected cells, viral gene expression is initiated when the immediate-early, or alpha, genes are transactivated by the alpha gene trans-inducing factor (alpha TIF), a component of the infecting virion. The protein binds to one or more recognition elements (TAATGARAT) in the promoters of alpha genes via interaction with the cellular proteins Oct-1 and CFF. The alpha TIF of HSV (HSV-alpha TIF) is believed to subsequently accelerate the assembly of the transcription complex by direct contact between its carboxyl-terminal acidic activation domain and at least two components of the transcription apparatus, TAFII40 and TFIIB. Like its HSV counterpart, the alpha TIF of bovine herpesvirus (BHV) (designated BHV-alpha TIF) also transactivates alpha gene promoters and for full activity exhibits a requirement for its extended carboxyl-terminal region. Despite this requirement, there is a notable lack of homology to the carboxyl-terminal acidic activation domain of HSV-alpha TIF. We swapped the amino- and carboxyl-terminal domains of HSV-alpha TIF and BHV-alpha TIF to make chimeric proteins. Using these chimeras, we show that the carboxyl terminus of BHV-alpha TIF is insufficient for transactivation, which requires cooperative determinants in both the amino-terminal and carboxyl-terminal regions of the protein. We have previously shown that the amino-terminal determinant in BHV-alpha TIF displays reduced but significant independent transactivation potential. Interestingly, this amino-terminal determinant appears not to reside in the HSV-alpha TIF, which displays no independent amino-terminal activity. Furthermore, we show that the amino-terminal activation domain of BHV-alpha TIF may be able to act synergistically with the carboxyl-terminal activation domain of HSV-alpha TIF, since a chimeric protein containing both domains appeared to be more efficient at activating transcription than either alpha TIF. In addition, the amino terminus of HSV-alpha TIF could not restore activity when linked to the carboxyl terminus of BHV-alpha TIF, while the amino terminus of BHV-alpha TIF reconstituted an intact protein with potent activation potential. We also show that in fusions with the DNA binding domain of GAL4, full activity requires the entire BHV-alpha TIF, although both amino and carboxyl termini display some activity on their own. In contrast, for HSV-alpha TIF, the carboxyl terminus is sufficient and possibly even more potent than the entire protein, while the amino-terminus is devoid of activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The bovine herpesvirus alpha gene trans-inducing factor activates transcription by mechanisms different from those of its herpes simplex virus type 1 counterpart VP16. 763 62

Gastrointestinal Stromal Tumor (GIST) is the most common mesenchymal tumor of the digestive tract. GISTs develop with relatively high incidence in patients with Neurofibromatosis-1 syndrome (NF1). Mutational activation of KIT or PDGFRA is believed to be a driving force in the pathogenesis of familial and sporadic GISTs. Unlike those tumors, NF1-associated GISTs do not have KIT or PGDFRA mutations. Similarly, no mutational activation of KIT or PDGFRA has been identified in pediatric GISTs and in GISTs associated with Carney Triad and Carney-Stratakis Syndrome. KIT and PDGFRA-wild type tumors are expected to have lesser response to imatinib treatment. Recently, Carney Triad and Carney-Stratakis Syndrome -associated GISTs and pediatric GISTs have been shown to have a loss of expression of succinate dehydrogenase subunit B (SDHB), a Krebs cycle/electron transport chain interface protein. It was proposed that GISTs can be divided into SDHB- positive (type 1), and SDHB-negative (type 2) tumors because of similarities in clinical features and response to imatinib treatment. In this study, SDHB expression was examined immunohistochemically in 22 well-characterized NF1-associated GISTs. All analyzed tumors expressed SDHB. Based on SDHB-expression status, NF1-associated GISTs belong to type 1 category; however, similarly to SDHB type 2 tumors, they do not respond well to imatinib treatment. Therefore, a simple categorization of GISTs into SDHB-positive and-negative seems to be incomplete. A classification based on both SDHB expression status and KIT and PDGFRA mutation status characterize GISTs more accurately and allow subdivision of SDHB-positive tumors into different clinico-genetic categories.
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PMID:Succinate Dehydrogenase Subunit B (SDHB) Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists): Implications for the SDHB Expression Based Classification of Gists. 2147 27

Succinate dehydrogenase-deficient gastrointestinal stromal tumors (SDH-deficient GISTs) are a unique class of GIST defined by negative immunohistochemical staining for succinate dehydrogenase B (SDHB). SDH-deficient GISTs show distinctive clinical and pathologic features including absence of KIT and PDGFRA mutations, exclusive gastric location, common lymph node metastasis, a prognosis not predicted by size and mitotic rate, and indolent behavior of metastases. They may be syndromal with some being associated with the Carney Triad or germline SDHA, SDHB, SDHC, or SDHD mutations (Carney-Stratakis syndrome). It is normally recommended that genetic testing for SDHA, SDHB, SDHC, and SDHD be offered whenever an SDH-deficient GIST is encountered. However, testing for all 4 genes is burdensome and beyond the means of most centers. In this study we performed SDHA mutation and immunohistochemical analyses for SDHA on 10 SDH-deficient GISTs. Three showed negative staining for SDHA, and all of these were associated with germline SDHA mutations. In 2 tumors, 3 novel mutations were identified (p.Gln54X, p.Thr267Met, and c.1663+3G>C), none of which have previously been reported in GISTs or other SDH-associated tumors. Seven showed positive staining for SDHA and were not associated with SDHA mutation. In conclusion, 30% of SDH-deficient GISTs in this study were associated with germline SDHA mutation. Negative staining for SDHA can be used to triage formal genetic testing for SDHA when an SDH-deficient GIST is encountered.
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PMID:Loss of SDHA expression identifies SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. 2306 Mar 55

Traditional Chinese medicine (TCM) has a combined therapeutic result in cancer treatment by integrating holistic and local therapeutical effects, by which TCM can enhance the curative effect and reduce the side effect. In this study, we analyzed the effect of CFF-1 (alcohol extract from an anticancer compound Chinese medicine) on prostate cancer (PCa) cell lines and studied in detail the mechanism of cell death induced by CFF-1 in vitro and in vivo. From our data, we found for the first time that CFF-1 obviously arrested cell cycle in G1 phase, decreased cell viability and then increased nuclear rupture in a dose-dependent manner and finally resulted in apoptosis in prostate cancer cells. In molecular level, our data showed that CFF-1 induced inhibition of EGFR auto-phosphorylation and inactivation of EGFR. Disruption of EGFR activity in turn suppressed downstream PI3K/AKT and Raf/Erk signal pathways, resulted in the decrease of p-FOXO1 (Ser256) and regulated the expression of apoptosis-related and cycle-related genes. Moreover, CFF-1 markedly induced cell autophagy through inhibiting PI3K/AKT/mTOR pathway and then up-regulating Beclin-1 and LC-3II and down-regulating phosphorylation of p70S6K. In vivo, CFF-1-treated group exhibited a significant decrease in tumor volume compared with the negative control group in subcutaneous xenograft tumor in nude mice via inhibiting EGFR-related signal pathways. Thus, bio-functions of Chinese medicine CFF-1 in inducing PCa cell growth inhibition, autophagy, and apoptosis suggested that CFF-1 had the clinical potential to treat patients with prostate cancer.
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PMID:Traditional Chinese Medicine CFF-1 induced cell growth inhibition, autophagy, and apoptosis via inhibiting EGFR-related pathways in prostate cancer. 2953 17

Gastrointestinal stromal tumors (GISTs) arise from the intestinal pacemaker cells of Cajal. Wild-type gastrointestinal stromal tumors (WT-GIST) are a unique and uncommon subtype of GISTs that lack activating mutations in the tyrosine kinase c-KIT or platelet derived growth factor receptor alpha (PDGFRA) receptors. The lack of these growth-stimulating mutations renders tyrosine kinase receptor inhibitors, such as imatinib mesylate, relatively ineffective against these tumors. WT-GIST arises most commonly due to underlying alternate proliferative signals associated with germ-line, genetic mutations. WT-GIST frequently arises in patients with BRAF mutations, Carney's Triad or neurofibromatosis type-1 (NF-1). All patients with WT-GIST require a careful examination for germ-line mutations and very close observation for recurrent tumors. Surgery remains a mainstay therapy for these patients. This review aims to discuss the most recent data available on the diagnosis and treatment of WT-GIST.
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PMID:Approach to wild-type gastrointestinal stromal tumors. 3060 28

Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are characterized by the lack of mutations in KIT receptor tyrosine kinase complex and platelet derived growth factor receptor-alpha (PDGFRA) that are commonly found in the majority of GISTs. SDH-deficient GISTs comprise approximately 5%-10% of all GISTs. This subset may be associated with Carney Triad and Carney-Stratakis syndrome. SDH-deficient GISTs show unique demographic, radiologic, morphologic findings, clinical behavior, and treatment response. To our knowledge, the identification and characterization of this subset of GISTs have not yet been described in the cytopathology literature. By understanding the clinical as well as the other unique features of this tumor, in addition to the rapidly evolving identification of specific molecular alterations and targeted therapies, cytopathologists may play an important role in the diagnosis and work-up of these patients to allow clinicians to better manage and treat them. We present a young female with gastric SDH-deficient GIST diagnosed by fine-needle biopsy with supporting surgical pathology follow-up and molecular confirmation. This report suggests that the diagnosis of SDH-deficient GIST can be made on cytology in the appropriate clinical setting by using cytomorphologic features and demonstrating SDH loss by IHC on the cell block. In addition, molecular testing may be possible on the cytology cell block or supernatant to confirm the diagnosis.
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PMID:Succinate dehydrogenase-deficient gastrointestinal stromal tumor of stomach diagnosed by endoscopic ultrasound-guided fine-needle biopsy: Report of a distinct subtype in cytology. 3287 Jun 1