title: Fibroblast growth factor rescues brain endothelial cells lacking presenilin 1 from apoptotic cell death following serum starvation.
abstract: Presenilin 1 (Psen1) is important for vascular brain development and is known to influence cellular stress responses. To understand the role of Psen1 in endothelial stress responses, we investigated the effects of serum withdrawal on wild type (wt) and Psen1-/- embryonic brain endothelial cells. Serum starvation induced apoptosis in Psen1-/- cells but did not affect wt cells. PI3K/AKT signaling was reduced in serum-starved Psen1-/- cells, and this was associated with elevated levels of phospho-p38 consistent with decreased pro-survival AKT signaling in the absence of Psen1. Fibroblast growth factor (FGF1 and FGF2), but not vascular endothelial growth factor (VEGF) rescued Psen1-/- cells from serum starvation induced apoptosis. Inhibition of FGF signaling induced apoptosis in wt cells under serum withdrawal, while blocking γ-secretase activity had no effect. In the absence of serum, FGF2 immunoreactivity was distributed diffusely in cytoplasmic and nuclear vesicles of wt and Psen1-/- cells, as levels of FGF2 in nuclear and cytosolic fractions were not significantly different. Thus, sensitivity of Psen1-/- cells to serum starvation is not due to lack of FGF synthesis but likely to effects of Psen1 on FGF release onto the cell surface and impaired activation of the PI3K/AKT survival pathway.
authors.affiliation: General Medical Research Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gama Sosa
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: De Gasperi
authors.affiliation: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Geriatrics and Palliative Care, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Hof
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, New York, USA.|Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Elder
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002470:Cell Survival; D016895:Culture Media, Serum-Free; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000235:genetics*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D016895:Culture Media, Serum-Free; D053764:Presenilin-1; D042461:Vascular Endothelial Growth Factor A; C580804:presenilin 1, mouse; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt