Sequence 990 (wtNRAS)

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Sequence wtNRAS
Target NRAS ( Homo sapiens )
Description Neuroblastoma RAS viral ( v-ras ) oncogene homolog

Ensembl: ENSG00000019991 UniGene: Hs.486502 EntrezGene: 4893 Ensembl Chr7: 81169381 - 81237388 Strand: -1 GO terms: 0000187 0000902 0001837 0001889 0004252 0005509 0005515 0005575 0006508 0006916 0007067 0007596 0008083 0048012 0051450

Design siRNA
Chemistry RNA
Sequence siRNA sense (23b) CAAGAAGAGTACAGTGCCATGTT / siRNA antisense (23b) CATGGCACTGTACTCTTCTTGTT
Application gene silencing
Name wtNRAS

References

Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells.Eskandarpour M, Kiaii S, Zhu C, Castro J, Sakko AJ, Hansson J.Int J Cancer. 2005 May 20;115(1) :65-73.

Intrathecal Injections in Children With Spinal Muscular Atrophy: Nusinersen Clinical Trial Experience. Hache M, Swoboda KJ, Sethna N, Farrow-Gillespie A, Khandji A, Xia S, Bishop KM. J Child Neurol. 2016 Jun;31(7):899-906. PubMed:26823478

Comments

Background

Gene Function. Kilby et al. (1996) found that the protein and mRNA for both hepatocyte growth factor and its receptor (MET) are present in third trimester placentas, suggesting that HGF serves as a paracrine mediator to control placental development and growth.

B cells develop in the bone marrow from progenitor cells that have been designated pre-pro-B cells, pro-B cells (no immunoglobulin, or Ig, chains chosen), pre-B cells (which have selected a heavy chain but not a light chain), and finally B cells (which express both heavy and light chains of the Ig molecule). Differentiation of pre-pro-B cells to pro-B cells requires signaling through IL7 receptor (IL7R; 146661) mediated by the pre-pro-B cell growth-stimulating factor (PPBSF), which consists of IL7 (146660) and a 30-kD protein cofactor. By amino acid sequencing and RT-PCR analysis, Lai and Goldschneider (2001) determined that the PPBSF cofactor is the 30-kD beta chain of HGF (HGFB) produced independently of the 60-kD alpha chain of HGF. Formation of an IL7-HGFB heterodimer requires the presence of heparin sulfate. Functional analysis indicated that either IL7 or HGFB can maintain the viability of pre-pro-B cells, but only the heterodimer can stimulate their proliferation and differentiation into pro-B cells. Lai and Goldschneider (2001) concluded that PPBSF is a novel form of cytokine, a hybrid cytokine, consisting of the bioactive components of 2 unrelated cytokines. They proposed that through its heparin-binding and mitogenic properties, HGFB enables IL7 to participate in cognate interactions at the stromal cell surface and transduce signals effectively at low levels of IL7R.

To explore the role of sinusoidal endothelial cells in the adult liver, LeCouter et al. (2003) studied the effects of VEGF receptor (VEGFR1; 165070) activation on mouse hepatocyte growth. Delivery of VEGFA (192240) increased liver mass in mice but did not stimulate growth of hepatocytes in vitro unless liver sinusoidal endothelial cells were also present in the culture. HGF was identified as one of the liver sinusoidal endothelial cell-derived paracrine mediators promoting hepatocyte growth. Selective activation of VEGFR1 stimulated hepatocyte but not endothelial proliferation in vivo and reduced liver damage in mice exposed to a hepatotoxin.

Carrolo et al. (2003) demonstrated that wounding of hepatocytes by migration of sporozoites of the rodent malarial parasite Plasmodium berghei induced secretion of HGF, which rendered hepatocytes susceptible to infection. Infection depended on activation of the HGF receptor, MET (164860), by secreted HGF. The malaria parasite exploited MET not as a primary binding site, but as a mediator of signals that made host cells susceptible to infection. HGF/MET signaling induced rearrangements of the host-cell actin cytoskeleton that were required for early development of parasites within hepatocytes.

Kaushansky and Kappe (2011) sought to determine if the mechanism of HGF induction by P. berghei described by Carrolo et al. (2003) applied to other Plasmodium species. They were able to reproduce the findings with P. berghei, but not with another rodent malaria parasite, P. yoelii, or with the human parasite, P. falciparum. Rodriguez and Mota (2011) concurred with the findings, but noted that the different rodent models remain useful in understanding the mechanisms underlying Plasmodium infection and contribute to future strategies to combat malaria.

Animal Model. Schmidt et al. (1995) and Uehara et al. (1995) produced targeted disruption of the HGF gene in mice and found that mice lacking the gene product fail to develop completely and die in utero. The mutation affects the embryonic liver, which is reduced in size and shows extensive loss of parenchymal cells. In addition, development of the placenta, particularly of trophoblast cells, is impaired. HGF/SF is thought to mediate a signal exchange between the mesenchyme and epithelia during mouse development. Both the HGF gene and the gene for its receptor, the product of the MET protooncogene (164860), are expressed in many tissues during embryonic development and in the adult. The findings of these studies indicate that HGF/SF is an essential mediator of allantoic mesenchyme-trophoblastic epithelia interaction required for placental organogenesis.

Maina et al. (1996) reported that HGF and MET are determinants of placenta, liver, and muscle development. They demonstrated that Met function in vivo requires signaling via 2 C-terminal tyrosines. For this purpose they introduced point mutations into the multifunctional docking sites of the mouse Met receptor (Y(1349)VHVNATY(1356)VNV) using the 'knock in' approach described by Hanks et al. (1995). These 2 phosphotyrosines in the C-terminal tail act as multifunctional docking sites for SH2-containing effectors. Maina et al. (1996) demonstrated that mutation of both of these residues in the mouse genome caused embryonal death with placental liver and limb muscle defects, mimicking the phenotype of Met-null mutants. They noted that the Y(1356)VNV motif in particular binds Grb2 (108355) and links the receptor with Ras (see 190020). They disrupted the consensus sequences for Grb2 binding and reported that development proceeded to term without affecting placenta and liver but caused a striking reduction in limb muscle coupled to a generalized deficit of secondary fibers. Maina et al. (1996) concluded that these data showed tissue-specific differences in MET signaling and revealed a novel role for HGF in late myogenesis.

Murine melanocytes ordinarily are confined to hair follicles. The skin of transgenic mice in which a metallothionein gene promoter forces the overexpression of Hgf/Sf has melanocytes in the dermis, epidermis, and dermal-ectodermal junction, and is thus more akin to human skin. Noonan et al. (2001) subjected albino Hgf/Sf transgenic mice and wildtype littermates to erythemal ultraviolet irradiation at 3.5 days of age, 6 weeks of age, or both. A single neonatal dose, which was 30-fold lower than the total ultraviolet dose administered previously to adult mice, was sufficient to induce melanoma in Hgf/Sf-transgenic mice after a relatively short latent period and with high cumulative incidence. This neonatal dose roughly corresponds to a sunburning dose of natural sunlight at midlatitudes in midsummer. Melanoma development in the transgenic mice after ultraviolet irradiation at both 3.5 days and 6 weeks was indistinguishable from that seen after only a single exposure at 3.5 days, whereas a similar dose at 6 weeks was not tumorigenic. However, the second exposure to ultraviolet light increased the multiplicity of melanocytic lesions as well as the incidence of nonmelanocytic tumors, including squamous cell carcinoma and sarcoma. Melanomas were not seen in either nontransgenic or untreated transgenic mice during the course of the experiment.

Using in situ hybridization and immunoblotting, Powell et al. (2001) detected expression of Hgf and Met in the cerebral wall and ganglionic eminence of the developing mouse forebrain. Using conditioned media and forebrain explants for scatter assays, Powell et al. (2001) concluded that the forebrain exhibits regionally specific motogenic activity attributable to Hgf. Powell et al. (2001) hypothesized that HGF is a key molecular constituent in guiding interneuron migration from the ganglionic eminence to the cerebral cortex.

Jin et al. (2004) found that overexpression of HGF in the retinal pigment epithelium (RPE) in rabbits induced chronic serous retinal detachment with subretinal proliferation of RPE.

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