Disease relevance of RBM9

• In addition, RTA, a fragment of Pseudomonas exotoxin A (PE38-lys), and fibronectin also block the binding of the mouse IgG-RTA peptide to ECs, suggesting that an (x)D(y) motif is exposed on all three molecules [1].
• Principal role of TRAP/mediator and SWI/SNF complexes in Kaposi's sarcoma-associated herpesvirus RTA-mediated lytic reactivation [2].
• An immunotoxin composed of an antibody to the human transferrin receptor (454A12) and ricin A chain (RTA) was shown to inhibit the growth of NIH:OVCAR-3 tumors in a nude mouse model of human ovarian cancer [3].
• An Escherichia coli expression system was used to produce recombinant ricin A chain (RTA) and RTA modified either by the addition of a carboxyl-terminal endoplasmic reticulum retrieval sequence Lys-Asp-Glu-Leu (RTAKDEL) or a nonfunctional analogue Lys-Asp-Glu-Ala (RTAKDEA) [4].
• These studies demonstrate for the first time the importance of CD3+ and CD5+ cells in diabetes onset in the low-dose STZ/IFN-gamma model and show that anti-CD3, anti-CD3 RTA, or anti-CD5 RTA may be useful in vivo for the treatment of diabetes or perhaps other T-cell-mediated autoimmune diseases [5].

High impact information on RBM9

• Consequently, these modifications strongly repressed RTA-mediated transcriptional activation by inhibiting its recruitment onto the promoters of virus lytic genes [6].
• Here we demonstrate that KSHV RTA recruits CBP, the SWI/SNF chromatin remodeling complex, and the TRAP/Mediator coactivator into viral promoters through interactions with a short acidic sequence in the carboxyl region and that this recruitment is essential for RTA-dependent viral gene expression [2].
• Hence, the control of RTA activity should play an important role in the maintenance of viral latency [6].
• Intracellular ricin and immunotoxin trafficking has been difficult to study as only one to two cytosolic ricin A chain (RTA) molecules are sufficient to cause cell death [7].
• Ammonium chloride had little effect on ricin or RI7/217-RTA cytotoxicity, but increased TF-RTA cytotoxicity against all hybridomas [7].

Chemical compound and disease context of RBM9

• Furthermore, RTA-induced expression of CD21 glycoprotein, which is an EBV receptor, efficiently facilitated EBV infection [8].
• Human diferric Tfn linked to RTA demonstrated the highest cytotoxic activity, being about 5,000 times more toxic than RTA alone for glioma cells and about 6,000 times more toxic for Jurkat cells in the presence of the carboxylic ionofore monensin [9].
• Tfn-RTA was over 100,000 times more potent than the chemotherapeutic agent BCNU in reducing glioma cell survival in vitro [9].
• We established cell clones from BJAB cells and replication-deficient BCBL-1 cells in which KSHV RTA expression was controlled by an inducible promoter of the tetracycline-based Tet-Off expression system [10].
• A unique 53-year-old male patient is described in whom aldosterone-refractory hyperkalemia and renal tubular acidosis/RTA/ was due to chronic interstitial nephritis associated with peritubular hyaline deposits in the distal nephron [11].

Biological context of RBM9

• Monensin abrogates the ricin-resistant phenotype when RTA is linked to RI7/217, but not RTB [7].
• These RTA molecules can enter mammalian cells by fluid phase endocytosis [4].
• The RTA is an immediate-early gene product, it is the initial activator of expression of a multitude of viral and cellular genes that have been implicated in the replication of HHV-8 and pathogenesis of KS [12].
• The predicted amino acid sequence is 95% identical to the corresponding rat and bovine receptors and 25% and 22% identical, respectively, to the receptors encoded by the RTA and MAS genes [13].
• Modulation of transactivation, through alternate RTA-protein, or RTA-promoter interactions, is hypothesized to participate in the selective tissue tropism and differential pathogenesis observed in KS [12].

Anatomical context of RBM9

• Previous studies (R.J. Youle and M. Colombatti, J. Biol. Chem., 262: 4676-4882, 1987) using anti-ricin hybridomas identified the secretory pre-Golgi as a critical site for RTA intoxication [7].
• RTAKDEL was significantly more cytotoxic than either RTA or RTAKDEA to both Vero cells and HeLa cells (250- and 10-fold, respectively), despite the fact that all these RTA molecules had comparable enzymatic activities [4].
• These results indicate that the added KDEL sequence facilitated RTA entry into the cytosol [4].
• Reconstitution of translocation-competent proteoliposomes from detergent-solubilized membranes of endoplasmic reticulum- and Golgi-enriched fractions provides a convenient cell-free system to study the mechanism of RTA translocation [14].
• Ricin in which the RTA moiety contained the disulfide bond was 15-18-fold less cytotoxic to HeLa or Vero cells than ricin in which the RTA did not contain the stabilizing disulfide cross-link [15].

Associations of RBM9 with chemical compounds

• We report here the isolation of a protein, denoted RTA for repressor of tamoxifen transcriptional activity, which contains an RNA recognition motif and interacts with the receptor N-terminal activation domain [16].
• These results demonstrate that the recruitment of CBP, SWI/SNF, and TRAP/Mediator complexes by RTA is the principal mechanism to direct well-controlled viral gene expression and thereby viral lytic reactivation [2].
• Wild type ricin A chain (RTA) contains two cysteine residues (Cys171 and Cys259) [15].
• In the presence of glutathione and protein disulfide isomerase, this RTA variant reassociated with RTB to form ricin holotoxin [15].
• IT was made by crosslinking anti-CD3 to a low oligosaccharide-containing fraction of purified ricin toxin A chain (RTA; a catalytic inhibitor of protein synthesis) with a stabilized derivative of 2-iminothiolane [5].

Analytical, diagnostic and therapeutic context of RBM9

• Western blot analysis of soluble leaf extracts using anti-ricin a-chain (RTA) antibodies identified 34- and 32-kDa proteins, which were electrophoretically indistinguishable from castor seed RTA [17].
• We have used site-directed mutagenesis of RTA cDNA to convert Cys171 to Ser and to introduce a disulfide bond into RTA by converting Ser215 and Met255 to Cys residues [15].
• AP1 transcription factors binding to the RTA promoter in electrophoretic mobility shift assays were readily detected in the infected cell nuclear extracts which were significantly reduced by ERK inhibition [18].
• Finally, RTA also proved to physically interact with both C/EBPalpha and RAP, as assayed both in vitro and by immunoprecipitation [19].
• Induction of endogenous KSHV RTA mRNA in PEL cells by exogenously introduced C/EBPalpha was confirmed by reverse transcription-PCR analysis and by double-label indirect immunofluorescence assays [20].

References