Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer is a genetic disease in which somatic mutations in the KRAS proto-oncogene are detected in a majority of tumors. KRAS mutations represent an early event during pancreatic tumorigenesis, crucial for cancer initiation and progression. Recent studies, including comprehensive sequencing of the pancreatic cancer exome, have implicated the involvement of a number of additional core signaling pathways during pancreatic tumorigenesis. Improving our understanding of genetic interactions between KRAS and these additional pathways represents a critical challenge, as these interactions may provide novel opportunities for diagnosis and treatment. However, studying these interactions requires the expression of multiple transgenes in relevant cell types, an effort that has proven very difficult to achieve using gene targeted mice and is also technically challenging in zebrafish. Based on the ability of the Gal4 transcriptional activator to drive the expression of multiple transgenes under regulation of UAS (upstream activator sequence) regulatory elements, the Gal4/UAS system represents an attractive strategy for the study of genetic interactions. In this chapter, we review our experience using the Gal4/UAS system to model KRAS-initiated pancreatic cancer in zebrafish, as well as our early efforts using this system to study the influence of other cooperating oncogenes. We also describe techniques used to identify and characterize pancreatic tumors in adult transgenic fish.
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PMID:Screening pancreatic oncogenes in zebrafish using the Gal4/UAS system. 2195 38

Pancreatic ductal adenocarcinoma (PDAC) continues to be a lethal disease with no efficacious treatment modalities. The incidence of PDAC is expected to increase, at least partially because of the obesity epidemic. Increased efforts to prevent or intercept this disease are clearly needed. Mutations in KRAS are initiating events in pancreatic carcinogenesis supported by genetically engineered mouse models of the disease. However, oncogenic KRAS is not entirely sufficient for the development of fully invasive PDAC. Additional genetic mutations and/or environmental, nutritional, and metabolic stressors, e.g. inflammation and obesity, are required for efficient PDAC formation with activation of KRAS downstream effectors. Multiple factors "upstream" of KRAS associated with obesity, including insulin resistance, inflammation, changes in gut microbiota and GI peptides, can enhance/modulate downstream signals. Multiple signaling networks and feedback loops "downstream" of KRAS have been described that respond to obesogenic diets. We propose that KRAS mutations potentiate a signaling network that is promoted by environmental factors. Specifically, we envisage that KRAS mutations increase the intensity and duration of the growth-promoting signaling network. As the transcriptional activator YAP plays a critical role in the network, we conclude that the rationale for targeting the network (at different points), e.g. with FDA approved drugs such as statins and metformin, is therefore compelling.
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PMID:KRAS, YAP, and obesity in pancreatic cancer: A signaling network with multiple loops. 2907 5

The ovary is surrounded by a whitish layer of mesodermally derived ovarian surface epithelium (OSE) that lines the intraembryonic celom and comprises simple squamous to cuboidal to low pseudostratified columnar epithelial cells. Its integrity is maintained by simple desmosomes, incomplete tight junctions, several integrins and cadherins. Recent research has found that ovarian stem cells (OSCs) exist within the OSE and may be responsible for both neo-oogenesis and ovarian cancer during adult life. The factors determining whether OSCs undergo neo-oogenesis or ovarian cancer are of great interest to researchers and clinicians. Accumulating evidence suggests the mechanism for the decision of ovarian surface epithelial stem cells to undergo either neo-oogenesis or ovarian cancer transformation may comprise both internal and external factors. Here, we review recent progress on how the internal factors, including genes, signaling pathways and lncRNA: OSE stem cells mediate the development and progression of ovarian cancer through various genes such as p53, KRAS, BRAF, and PTEN, and mutations in PIK3CA, and through various signaling pathways, including TGF-B pathway, Wnt signaling pathway, Notch signaling pathway, NF-kB signal transducer and transcriptional activator 3 (STAT3) pathway and Hedghog (HH) pathway. A series of expressions of IncRNA have changed in epithelial ovarian cancer tissues and cell lines compared to normal ovarian tissues and cell lines. As well as external factors, including incessant ovulation, gonadotropin and chronicinflammation: Frequent ovulation, without long-term dormancy, increases the risk of illness, because repeated rupture and repair at the ovulation site provides an opportunity for the accumulation of genetic aberrations; FSH affects all aspects of ovarian cancer metastasis, such as inhibition of apoptosis, through Induction of increased expression of VEGFA (VEGF) to support tumor growth, promote vascular growth, and possibly alter certain oncogenic pathways, thereby promoting proliferation and invasive phenotypic inflammation contributes to tumorigenesis, which help determine whether OSCs undergo neo-oogenesis or ovarian tumorigenesis. Understanding this issue is critical for developing novel strategies for premature ovarian failure and ovarian cancer prevention and therapy.
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PMID:Mechanism for the Decision of Ovarian Surface Epithelial Stem Cells to Undergo Neo-Oogenesis or Ovarian Tumorigenesis. 3033 65