Disease relevance of Rasl2-9

• Thus Lps/Ran is an important target for LPS-mediated signal transduction, and the Lps(d)/Ran gene may be useful as a therapeutic sequence in gene therapy for endotoxemia and septic shock [1].
• However, the Ran-dependent nuclear import of NTD was efficiently competed by excess amounts of the nuclear localization signal (NLS) peptide from simian virus 40 large T antigen, suggesting that import is mediated by the classical NLS pathway [2].
• By means of the yeast two-hybrid system, we have discovered a novel physical interaction between the adenovirus E1A oncoprotein and Ran, a small GTPase which regulates nucleocytoplasmic transport, cell cycle progression, and mitotic spindle organization [3].
• We have adopted a novel approach to silence or ablate GHRH neurons, using a modified H37A variant of the influenza virus M2 protein ((H37A)M2) [4].
• Passively transferred monoclonal antibody to the M2 protein inhibits influenza A virus replication in mice [5].

High impact information on Rasl2-9

• In support of this hypothesis, adoptive transfer of an M2-specific CD8(+) T cell line reduced the initial load of latently infected cells, although not the long-term load [6].
• In addition to nucleocytoplasmic transport, the Ran-Crm1 network is involved in regulating centrosome duplication to ensure the formation of a bipolar spindle [7].
• Moreover, ARAN1, when injected into the cultured cells induces the accumulation of endogenous Ran in the cytoplasm and prevents the nuclear import of SV-40 T-antigen nuclear localization signal substrates [8].
• Transcription of one MHV-68 gene, that encoding the hypothetical M2 protein, was detected in virtually all latently infected S11 cells and in splenocytes of latently infected mice, but not in lytically infected fibroblasts [9].
• Furthermore, an epitope was identified in the predicted M2 protein that is recognized by CD8(+) T cells from infected mice and a cytotoxic T lymphocyte line that recognizes this epitope killed S11 cells, indicating that the M2 protein is expressed during latent infection and is a target for the host cytotoxic T lymphocyte response [9].

Biological context of Rasl2-9

• We have now characterized patterns of Ran gene expression in the mouse [10].
• Our results indicate that Ran has a cell cycle-dependent localization and may have regulatory roles in cell cycle progression and microtubule organization in mouse oocytes, fertilized eggs and early embryos [11].
• After sperm penetration, Ran dispersed with the extrusion of the second polar body and gradually concentrated in the male and female pronuclei thereafter [11].
• At pro-metaphase of meiosis I, Ran distributed throughout the cell, but predominantly concentrated around the condensed chromosomes [11].
• Of importance, purified tumor-associated macrophages display a similar M2 phenotype and are suppressive for antitumor CTLs, via a mechanism that can be almost completely reversed by PPARgamma ligands [12].

Anatomical context of Rasl2-9

• In testis, this Ran mRNA was abundant, as were other larger transcripts [10].
• Previous studies of Ran proteins have utilized cell-free systems, yeasts, and cultured mammalian cells [10].
• Serum starvation suppressed Ran gene transcription in mouse 3T3 cells [10].
• Real-time RT-PCR experiments demonstrated that the expression of Ran/M1 and Ran/M2 increased in pachytene spermatocytes with progressive transcript accumulation until they reached the round spermatid stage, in the seminiferous epithelium of adults [13].
• In this experiment, we investigated the localization and possible roles of Ran during mouse oocyte meiotic maturation, fertilization and early cleavage by using confocal laser scanning microscopy, antibody microinjection and microtubule disturbance [11].

Associations of Rasl2-9 with chemical compounds

• By functional cDNA expression cloning, we have previously established that Ran is important in lipopolysaccharide (LPS) signaling [14].
• Translational control of putative protooncogene Nm23-M2 by cytokines via phosphoinositide 3-kinase signaling [15].
• Moreover, leptomycin B, which inhibits NES-mediated export, was also without effect. tsBN2 cells contain a thermosensitive RCC1 protein (Ran GTP exchange protein) [16].
• In this study, we used two approaches to demonstrate that expression of an H-2Kd-restricted nonameric peptide (Ser Tyr Ile Gly Ser Ile Asn Asn Ile) corresponding to M2 residues 82 to 90 is necessary and sufficient to induce protective TCD8+ responses [17].
• We investigated the effect of cyclic AMP on M2 messenger RNA concentrations using RNA from exponentially growing and elutriated, cell cycle-enriched populations [18].

Analytical, diagnostic and therapeutic context of Rasl2-9

• These data represent the first description of a latent antigen-specific immune response in this model, and suggest that vaccination with latent antigens such as M2 may be capable of modulating latent gammaherpesvirus infection [6].
• In immunoblotting analysis, a monoclonal antibody against recombinant human Ran, designated ARAN1, was found to recognize an epitope in the COOH-terminal domain of Ran [8].
• A novel human protein with a molecular mass of 55 kD, designated RanBPM, was isolated with the two-hybrid method using Ran as a bait [19].
• By immunofluorescence, Ran is accumulated on the chromosomes of meiosis-II-arrested Xenopus eggs [20].
• Finally, a mutant lacking both the transmembrane and cytoplasmic domains of M2 protein grew poorly in cell culture and showed no growth in mice [21].

References