Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0403608 (ureter)
 9,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular mechanisms that lead to congenital anomalies of kidneys and the lower urinary tract (CAKUT) are poorly understood. To elucidate the molecular basis for signaling specificity of GDNF-mediated RET signaling in kidney development, we characterized mice that exclusively express either the human RET9 or RET51 isoform, or express these isoforms with individual mutations in docking tyrosines for PTB and SH2-domain-containing adaptors Src (Y981), PLCgamma (Y1015), and Shc (Y1062). Our results provide evidence for differential and isoform-specific roles of these docking sites in murine kidney development. Homozygous Ret(RET9) and Ret(RET51) mice were viable and show normally developed kidneys, indicating redundant roles of human RET isoforms in murine kidney development. In the context of the RET51 isoform, only mutation of the docking Tyr 1015 (Y1015F) resulted in severe renal anomalies. These included bilateral megaureters and multicystic kidneys that were caused by supernumerary ureteric buds that fail to separate from the wolffian duct as well as decreased branching morphogenesis. Similar kidney and ureter defects were observed in RET9(Y1015F) mice that contain the Y1015F mutation in the RET9 isoform. Interestingly, loss of RET9(Y1062)-mediated AKT/MAPK activation resulted in renal agenesis or kidney rudiments, whereas mutation of this residue in RET51 had no obvious effect on AKT/MAPK activity and renal development. These results reveal novel roles of key RET-dependent signaling pathways in embryonic kidney development and provide murine models and new insights into the molecular basis for CAKUT.
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PMID:Critical and distinct roles for key RET tyrosine docking sites in renal development. 1645 4

Heterozygous loss of Bmp4 results both in humans and mice in severe malformation of the urinary tract. These defects have at least partially been attributed to loss of expression of Bmp4 in the ureteric mesenchyme, yet the cellular and molecular function of this signal as well as its effector pathways in this tissue have remained incompletely resolved. Here, we show that mice with a conditional deletion of Bmp4 in the ureteric mesenchyme exhibited hydroureter and hydronephrosis at newborn stages due to functional and physical ureter obstruction. Proliferation in both the mesenchymal and epithelial progenitor pools was severely reduced and smooth muscle cell and urothelial differentiation programs were not activated. Epithelial expression of P-ERK1/2, P-AKT and P-P38, and mesenchymal expression of P-SMAD1/5/9, P-P38 and P-AKT were abrogated. Pharmacological inhibition and activation experiments in ureter cultures defined AKT as the most relevant downstream effector for epithelial and mesenchymal proliferation as well as for epithelial differentiation. Epithelial proliferation and differentiation were also influenced by P-38 and ERK1/2, while SMAD signaling, together with AKT and P-38, were required for smooth muscle cell differentiation. Our analysis suggests that BMP4 is the signal that couples the proliferation and differentiation programs in the epithelial and mesenchymal tissue compartments of the developing ureter by different downstream effectors, most importantly AKT and SMAD.
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PMID:BMP4 uses several different effector pathways to regulate proliferation and differentiation in the epithelial and mesenchymal tissue compartments of the developing mouse ureter. 2865 68

Epithelial ovarian cancer (EOC) is the fifth most common cause of cancer mortality among women. At present, EOC is treated with one or in a combination of treatments, commonly debulking surgery, combining a platinum-based and a taxane-based therapy; however, the patients have a risk of injury to the bowel, bladder, ureter, and vessels during surgery and many of them suffer from severe adverse effects caused by chemotherapy. Pharmaceutical inhibition of cyclooxygenase (COX) might be an important therapeutic tool in cancer treatment, as COX contributes to cancer progression by upregulating the levels of downstream metabolites. In this review article, we have discussed the role of COX in cancer progression and the therapeutic use of COX inhibitors in the treatment of EOC with subsequent clinical studies and future management. Usually, gonadotropins can promote prostaglandin E2 production in EOC cells via COX-1 and -2 upregulations through the PI3K/AKT signaling pathway. Several reports have shown that treatment of EOC cells with COX-1- and COX-2-specific inhibitors exhibits a therapeutic effect on EOC both in vitro and in vivo. However, more clinical investigations are needed to develop therapeutic COX inhibitors for the prevention and treatment of EOC without adverse effects.
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PMID:Cyclooxygenase Inhibitors in Epithelial Ovarian Cancer Treatment. 2972 50