Abstract:The nuclear transcription factor E2F1 plays an important role in modulating neuronal death in response to excitotoxicity and cerebral ischemia. Here, by comparing gene expression in brain cortices from E2F1 ؉/؉ and E2F1 ؊/؊ mice using a custom high-density DNA microarray, we identified a group of putative E2F1 target genes that might be responsible for ischemia-induced E2F1-dependent neuronal death. Neuropilin 1 (NRP-1), a receptor for semaphorin 3A-mediated axon growth cone collapse and retraction, was confir… Show more
“…Therefore, these data indicate that E2F1 downregulates the expression level of pro-angiogenic VEGF xxx transcripts. To test whether this effect was specific for VEGF xxx transcripts, we analysed the expression level of neuropilin-1, the co-receptor of VEGFR-2 that was recently identified as a new E2F1 transcriptional target gene (Jiang et al, 2007). Upon E2F1 overexpression, we found that the level of neuropilin-1 mRNA was slightly increased, whereas the expression of neuropilin-2 was not affected (Figure 1a, lower panel).…”
Section: E2f1 Downregulates the Expression Of Pro-angiogenic Vegf XXXmentioning
“…Therefore, these data indicate that E2F1 downregulates the expression level of pro-angiogenic VEGF xxx transcripts. To test whether this effect was specific for VEGF xxx transcripts, we analysed the expression level of neuropilin-1, the co-receptor of VEGFR-2 that was recently identified as a new E2F1 transcriptional target gene (Jiang et al, 2007). Upon E2F1 overexpression, we found that the level of neuropilin-1 mRNA was slightly increased, whereas the expression of neuropilin-2 was not affected (Figure 1a, lower panel).…”
Section: E2f1 Downregulates the Expression Of Pro-angiogenic Vegf XXXmentioning
“…For example, in HeLa cells NRP-1 expression is controlled by SP1, AP1, and CCAAT box transcription factors, 42 whereas in neurons E2F1 factor binds directly to the endogenous NRP-1 promoter to positively regulate its expression. 43 Production of SHH ligand and pathway activity is related to NRP-1 expression, and NRP-1 knockdown leads to reduced SHH, Gli-1, and E-cadherin production in renal carcinoma cells. 26 Similarly, blockade of the SHH pathway leads to reduced expression of E-cadherin, b 1 integrin, and VEGF in EOC cells.…”
Section: Vegfr2 Rnai Knockdown Increases Eoc Malignancy Sai Adham Et Almentioning
Human epithelial ovarian cancer (EOC) is the most lethal neoplasm affecting the female genital tract, and is characterized by overexpression of vascular endothelial growth factor (VEGF) and growth as ascites. Anti-VEGF strategies are currently used in EOC therapy with promising results; however, molecular targeting of specific VEGF receptors on the cancer cells themselves has not been explored to date. We previously showed that activation of a VEGF/VEGFR2 signaling loop in EOC cells supports their survival in suspension, and short-term pharmacological inhibition of this loop increased EOC cell apoptosis in vitro. In this study, we stably knocked down VEGFR2 in OVCAR-3 and SKOV-3 EOC cells using short hairpin RNA (shRNA), an RNA interference strategy that could potentially overcome chemoresistance arising with angiogenic inhibitors. Unexpectedly, we observed an induction of more aggressive cellular behavior in transfected cells, leading to increased growth in mouse xenografts, enhanced accumulation of ascites, increased VEGF and neuropilin-1 (NRP-1) expression, and decreased expression of adhesion proteins, notably cadherins and integrins. Sonic hedgehog (SHH) pathways do not seem to be involved in the upregulation of NRP-1 message in VEGFR2 knockdown cells. Supporting our mouse model, we also found a significant increase in the ratio between NRP-1 and VEGFR2 with increasing tumor grade in 80 cases of human EOC. The change in EOC behavior that we report in this study occurred independent of the angiogenic response and shows the direct effect of VEGF blockade on the cancer cells themselves. Our findings highlight the possible confounding events that may affect the usefulness of RNAi in a therapeutic setting for disrupting EOC cell survival in ascites.
“…Besides its role in regulating neuronal morphology, accumulating evidence suggests that Sema3A induces neuronal apoptosis (Gagliardini and Fankhauser, 1999;Shirvan et al, 1999Shirvan et al, , 2002Ben-Zvi et al, 2006). Despite recent progress, whether Sema3A, Npn1 and plexins are physiologically relevant in developmental cell death in vivo, and the mechanisms underlying semaphorin-induced apoptosis, remain poorly understood (Ben-Zvi et al, 2006Jiang et al, 2007Jiang et al, , 2010Haupt et al, 2010). Here we identify Sema3A as a retrograde death signal for developing sympathetic neurons.…”
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