The higher prevalence and risk for Alzheimer's disease in women relative to men has been partially attributed to the precipitous decline in gonadal hormone levels that occur in women following the menopause. While considerable attention has focused on the consequence of estrogen loss, and thus, estrogen's neuroprotective potential, it is important to recognize that the menopause results in a precipitous decline in progesterone levels as well. In fact, progesterone is neuroprotective, although the precise mechanisms involved remain unclear. Based on our previous observation that progesterone elicits the phosphorylation of ERK and Akt, key effectors of the neuroprotective MAPK and PI3-K pathways, respectively, we determined if activation of either of these pathways was necessary for progesterone-induced protection. Using organotypic explants (slice culture) of the cerebral cortex, we found that progesterone protected against glutamate-induced toxicity. Further, these protective effects were inhibited by either the MEK1/2 inhibitor, UO126, or the PI-3K inhibitor, LY294002, supporting the requirement of both the MAPK and PI-3K pathways in progesteroneinduced protection. In addition, at a concentration and duration of treatment consistent with our neuroprotection data, progesterone also increased the expression of Brain-Derived Neurotrophic Factor (BDNF), at the level of both protein and mRNA. This induction of BDNF may be relevant to the protective effects of progesterone since inhibition of Trk signaling, using K252a, inhibited the protective effects of progesterone. Collectively, these data suggest that progesterone is protective via multiple and potentially related mechanisms.
Fibroblast growth factor (FGF) signaling mediates cell-to-cell communication in development and organ homeostasis in adults. Of the four FGF receptor (FGFR) tyrosine kinases, only FGFR4 is expressed in mature hepatocytes. Although FGFR1 is expressed by hepatic cell progenitors and adult nonparenchymal cells, ectopic expression is commonly observed in hepatoma cells. Here, we determined whether ectopic FGFR1 is a cause or consequence of hepatocellular carcinoma by targeting a constitutively active human FGFR1 to mouse hepatocytes. Livers of transgenic mice exhibited accelerated regeneration after partial hepatectomy but no signs of neoplastic or preneoplastic abnormalities for up to 18 months. However, in diethylnitrosamine-treated mice, the chronic FGFR1 activity promoted an incidence of 44% adenomas at 4 months and 38% hepatocellular carcinoma at 8 months. No adenoma or hepatocellular carcinoma was observed in diethylnitrosamine-treated wild-type (WT) livers at 4 or 8 months, respectively. At 10 and 12 months, tumorbearing livers in transgenic mice were twice the size of those in WT animals. Isolated hepatoma cells from the transgenic tumors exhibited a growth advantage in culture. Advanced hepatocellular carcinoma in the transgenic livers exhibited a reduced rate of necrosis. This was accompanied by a mean microvessel density of 2.7 times that of WT tumors and a markedly higher level of vascular endothelial growth factor. In cooperation with an initiator, the persistent activity of ectopic FGFR1 in hepatocytes is a strong promoter of hepatocellular carcinoma by driving cell proliferation at early stages and promoting neoangiogenesis at late stages of progression.
Kip1 is a key regulatory step in activation of the cyclin E/A-Cdk complex during the G 1 /S transition of the cell cycle, the results suggest a novel mitogenic pathway whereby FGF and other growth factors that activate FRS2 directly activate cyclin-dependent kinases. The fibroblast growth factor (FGF)1 family is a ubiquitously expressed transmembrane signaling family that elicits receptor-mediated regulatory effects on cell growth, function, differentiation, and death. The FGF ligands are single polypeptides consisting of 22 genetically distinct homologues, and the FGF receptors (FGFRs) are transmembrane tyrosine kinases encoded by four homologous gene products, which complex with pericellular matrix heparan sulfates independent of the FGF ligand (1, 2). Binding of FGF ligands to FGFR-heparan sulfate complexes activates the kinase activity and transmits regulatory signals to downstream signaling mediators or targets. Accumulating reports demonstrate that FGFRs elicit diverse regulatory activities that are cell type-and FGFR-specific as well as redundant among the four FGFRs. The molecular mechanisms that would explain both specificity and redundant activities are not well understood. Two proximal substrates (FRS1 and FRS2) interact with the activated FGFR tyrosine kinases that are tyrosine-autophosphorylated. FRS1 is phospholipase C␥, which binds to phosphorylated tyrosine 766 of FGFR1, and is phosphorylated by the kinase. Activation of FRS1 is not obligatory for the mitogenic activity of FGFR1 (3, 4). However, it is important for prostate epithelial cells to acquire a mitogenic response to FGFR1 and for other cellular activities stimulated by phospholipase C␥ (5).FRS2 (also called SNT1, for suc1-associating nuclear target protein 1) is an adaptor protein that is anchored to the plasma membrane by virtue of myristoylation at the N terminus (6 -8). FRS2 interacts with the intracellular juxtamembrane sequence of the FGFR through a conserved phosphotyrosine binding (PTB) domain adjacent to the C terminus of the myristoylation consensus sequence (9, 10). The PTB domain of FRS2 is homologous to and exhibits a similar three-dimensional structure as PTB domains of several other signaling adaptor proteins, including insulin receptor substrate 1. Phosphorylation of FRS2 in response to FGF treatment is associated with the FGF mitogenic signaling (6). The C-terminal half of FRS2 has multiple candidate phosphorylation sites as well as numerous signaling molecule binding sites, which include Grb2 that recruits upstream activators of the extracellular signal-regulated kinase 1/2 in the MAP kinase pathway. Therefore, FRS2 is considered an adaptor that connects FGFR to the MAP kinase pathway (5,(11)(12)(13)(14)(15). The fact that not all FGFR signaling is tightly associated with activation of the MAP kinase pathway (16, 17) prompted us to investigate alternative and potentially more direct means by which the FGFR transmits mitogenic signals.The interaction of FRS2 with p13 suc1
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.