Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ran binding protein RanBP1 is localized to the cytosol of interphase cells. A leucine-rich nuclear export signal (NES) near the C terminus of RanBP1 is essential to maintain this distribution. We now show that RanBP1 accumulates in nuclei of cells treated with the export inhibitor, leptomycin B, and collapse of the nucleocytoplasmic Ran:GTP gradient leads to equilibration of RanBP1 across the nuclear envelope. Low temperature prevents nuclear accumulation of RanBP1, suggesting that import does not occur via simple diffusion. Glutathione S-transferase (GST)-RanBP1(1-161), which lacks the NES, accumulates in the nucleus after cytoplasmic microinjection. In permeabilized cells, nuclear accumulation of GST-RanBP1(1-161) requires nuclear Ran:GTP but is not inhibited by a dominant interfering G19V mutant of Ran. Nuclear accumulation is enhanced by addition of exogenous karyopherins/importins or RCC1, both of which also enhance nuclear Ran accumulation. Import correlates with Ran concentration. Remarkably, an E37K mutant of RanBP1 does not import into the nuclei under any conditions tested despite the fact that it can form a ternary complex with Ran and importin beta. These data indicate that RanBP1 translocates through the pores by an active, nonclassical mechanism and requires Ran:GTP for nuclear accumulation. Shuttling of RanBP1 may function to clear nuclear pores of Ran:GTP, to prevent premature release of import cargo from transport receptors.
Mol Cell Biol 2000 May
PMID:Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1. 1077 40

Nuclear formation in Xenopus egg extracts requires cytosol and is inhibited by GTP gamma S, indicating a requirement for GTPase activity. Nuclear envelope (NE) vesicle fusion is extensively inhibited by GTP gamma S and two mutant forms of the Ran GTPase, Q69L and T24N. Depletion of either Ran or RCC1, the exchange factor for Ran, from the assembly reaction also inhibits this step of NE formation. Ran depletion can be complemented by the addition of Ran loaded with either GTP or GDP but not with GTP gamma S. RCC1 depletion is only complemented by RCC1 itself or by RanGTP. Thus, generation of RanGTP by RCC1 and GTP hydrolysis by Ran are both required for the extensive membrane fusion events that lead to NE formation.
Mol Cell 2000 Jun
PMID:GTP hydrolysis by Ran is required for nuclear envelope assembly. 1091 95

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene cause X-linked retinitis pigmentosa type 3 (RP3), a severe, progressive and degenerative retinal dystrophy eventually leading to complete blindness. RPGR is ubiquitously expressed, yet mutations in the RPGR gene lead to a retina-restricted phenotype. To date, all RP3 associated missense mutations that have been identified are located in the RCC1-homologous domain (RHD) of RPGR. To investigate the molecular pathogenesis of RP3, we screened retinal yeast two-hybrid libraries with the RHD of RPGR. We identified several alternatively spliced gene products, some with retina-restricted expression, that interact specifically with RPGR in vivo and in vitro. Thus, these proteins were named RPGR-interacting protein 1 (RPGRIP1) isoforms. They contain a C-terminal RPGR-interacting domain and stretches of variable coiled-coil domains homologous to proteins involved in vesicular trafficking. The interaction between RPGR and RPGRIP1 isoforms was impaired in vivo by RP3-associated mutations in RPGR. Moreover, RPGR and RPGRIP1 co-localize in the outer segment of rod photoreceptors, which is in full agreement with the retinitis pigmentosa phenotype observed in RP3 patients. The localization of RPGRIP1 at 14q11 makes it a strong candidate gene for RP16. These results provide a clue for the retina-specific pathogenesis in RP3, and hint towards the involvement of RPGR and RPGRIP1 in mediating vesicular transport-associated processes.
Hum Mol Genet 2000 Sep 01
PMID:The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors. 1095 48

Klotho protein is a novel beta-glucosidase-like protein produced predominantly in the kidney. The klotho mouse, which genetically lacks klotho gene expression, manifests various systemic phenotypes resembling aging. In the present study we succeeded in isolating a novel human protein structurally related to klotho protein. The protein possesses one beta-glucosidase-like domain and is 42% identical with klotho protein at the amino acid level. Unlike klotho protein, it possesses neither a signal sequence nor a transmembrane domain, suggesting that it is a cytosolic protein, and thus was termed cytosolic beta-glucosidase-like protein-1 (cBGL1). By Northern blot analysis cBGL1 mRNA was expressed most abundantly in the liver, followed by the small intestine, colon, spleen, and kidney. When klotho and cBGL1 gene expression was examined in renal cell carcinoma tissues, both klotho and cBGL1 mRNA levels in tumors were lower than those in nontumor regions, suggesting that renal epithelial cells may lose klotho and cBGL1 gene expression during the course of malignant transformation. In conclusion, we describe the primary structure and gene expression of a novel protein related to klotho protein.
J Mol Med (Berl) 2000
PMID:Molecular cloning and expression of a novel klotho-related protein. 1104 82

We made novel measurements of the influence of rest intervals and stimulation frequency on twitch contractions and on sarcoplasmic reticulum (SR) Ca(2+)-content (using rapid cooling contractures, RCCs) in isolated ventricular muscle strips from rat and rabbit hearts at a physiological temperature of 37 degrees C. In addition, the frequency-dependent relative contribution of SR Ca(2+)-uptake and Na(+)/Ca(2+)-exchange for cytosolic Ca(2+)-removal was assessed by paired RCCs. With increasing rest intervals (1-240 s) post-rest twitch force and RCC amplitude decreased monotonically in rabbit myocardium (after 240 s by 45+/-10% and 61+/-11%, respectively P<0. 05, n=14). In contrast, rat myocardium (n=11) exhibited a parallel increase in post-rest twitch force (by 67+/-16% at 240 s P<0.05) and RCC amplitude (by 20+/-14%P<0.05). In rabbit myocardium (n=11), increasing stimulation frequency from 0.25 to 3 Hz increased twitch force by 295+/-50% (P<0.05) and RCC amplitude by 305+/-80% (P<0.05). In contrast, in rat myocardium (n=6), twitch force declined by 43+/-7% (P<0.05), while RCC amplitude decreased only insignificantly (by 16+/-7%). The SR Ca(2+)-uptake relative to Na(+)/Ca(2+)-exchange (based on paired RCCs) increased progressively with frequency in rabbit, but not in rat myocardium (;66+/-2% at all frequencies). We conclude that increased SR Ca(2+)-load contributes to the positive force-frequency relationship in rabbits and post-rest potentiation of twitch force in rats. Decreased SR Ca(2+)-load contributes to post-rest decay of twitch force in rabbits, but may play only a minor role in the negative force-frequency relationship in rats. SR Ca(2+)-release channel refractoriness may contribute importantly to the negative force-frequency relationship in rat and recovery from refractoriness may contribute to post-rest potentiation.
J Mol Cell Cardiol 2000 Dec
PMID:Differences in Ca(2+)-handling and sarcoplasmic reticulum Ca(2+)-content in isolated rat and rabbit myocardium. 1111

Mutations in the von Hippel-Lindau (VHL) gene are involved in the family cancer syndrome for which it is named and the development of sporadic renal cell cancer (RCC). Reintroduction of VHL into RCC cells lacking functional VHL [VHL(-)] can suppress their growth in nude mice, but not under standard tissue culture conditions. To examine the hypothesis that the tumor suppressor function of VHL requires signaling through contact with extracellular matrix (ECM), 786-O VHL(-) RCC cells and isogenic sublines stably expressing VHL gene products [VHL(+)] were grown on ECMs. Cell-cell and cell-ECM signalings were required to elicit VHL-dependent differences in growth and differentiation. VHL(+) cells differentiated into organized epithelial sheets, whereas VHL(-) cells were branched and disorganized. VHL(+) cells grown to high density on collagen I underwent growth arrest, whereas VHL(-) cells continued to proliferate. Integrin levels were up-regulated in VHL(-) cells, and cell adhesion was down-regulated in VHL(+) cells during growth at high cell density. Hepatocyte nuclear factor 1alpha, a transcription factor and global activator of proximal tubule-specific genes in the nephron, was markedly up-regulated in VHL(+) cells grown at high cell density. These data indicate that VHL can induce renal cell differentiation and mediate growth arrest through integration of cell-cell and cell-ECM signals.
Mol Cell Biol 2001 Feb
PMID:VHL induces renal cell differentiation and growth arrest through integration of cell-cell and cell-extracellular matrix signaling. 1115 73

Leaf senescence is accompanied by the metabolism of chlorophyll (Chl) to nonfluorescent catabolites (NCCs). The pathway of Chl degradation comprises several reactions and includes the occurrence of intermediary catabolites. After removal of phytol and the central Mg atom from Chl by chlorophyllase and Mg dechelatase, respectively, the porphyrin macrocycle of pheophorbide (Pheide) a is cleaved. This two-step reaction is catalyzed by Pheide a oxygenase and RCC reductase and yields a primary fluorescent catabolite (pFCC). After hydroxylation and additional species-specific modifications, FCCs are tautomerized nonenzymically to NCCs inside the vacuole. Different subcellular compartments participate in Chl catabolism and, thus, transport processes across membranes are required. This review focuses on the catabolites and the individual reactions of Chl breakdown in higher plants. In addition, the pathway is compared to Chl conversion to red catabolites in an alga, Chlorella protothecoides. Finally, the significance and regulation of Chl degradation are discussed.
Cell Mol Life Sci 1999 Oct 15
PMID:Chlorophyll breakdown in higher plants and algae. 1121 60

Intratumoral administration of cytokine genes in order to achieve paracrine secretion of immunostimulatory cytokines and to create tumor vaccines in situ can avoid difficulties associated with the production of autologous and allogeneic vaccines, and toxicity related to systemic administration of cytokines. In this review, we summarize our experience with intratumoral administration of IL-2 cDNA/DMRIE/DOPE lipid complex in patients with metastatic renal cell carcinoma. An objective response rate of 14% was achieved in a phase I/II clinical trial and was confirmed in the low-risk subgroup of a phase II study. The achieved objective clinical responses (PR/CR) were long lasting. Application of PCR and immunohistochemistry in post-treatment tumor biopsies detected the IL-2 plasmid in addition to increased IL-2 expression in tumor cells and CD8 infiltration. Clinical trials employing higher doses of the plasmid in renal cell carcinoma patients with limited disease are ongoing.
Curr Opin Mol Ther 2001 Feb
PMID:Immunotherapy of renal cell carcinoma by intratumoral administration of an IL-2 cDNA/DMRIE/DOPE lipid complex. 1124 34

The von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene on human chromosome 3p25. It is characterized clinically by vascular tumors including benign hemangioblastomas of the cerebellum, spine, brain stem and retina. Clear-cell renal cell carcinoma is a frequent cause of death, occurring in up to 70% of patients with VHL. Pheochromocytomas occur in association with specific alleles (usually mutations as opposed to deletions), therefore a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members. The VHL gene coding sequence contains three exons. Two isoforms of mRNA exist, reflecting the presence or absence of exon 2. Tumors arise following the loss or inactivation of the wild-type allele in a cell. In initial studies approximately 20% of patients had large germline mutations detectable by Southern blot analysis, 27% had missense mutations and 27% had nonsense or frameshift mutations. Advances in mutation analysis now allow for a 100% mutation detection rate in families with definite VHL. Families may be characterized by the presence [type 2 (7-20% of families)] or absence (type 1) of pheochromocytomas. Most type 2 families are affected by missense mutations, whereas most type 1 families have deletions or premature termination mutations. The prognosis for the lifetime risk of pheochromocytoma can be estimated by determination of the underlying mutation even if there is no family history of VHL.
Hum Mol Genet 2001 Apr
PMID:Genotype-phenotype correlation in von Hippel-Lindau syndrome. 1125 10

Angiomyolipomas (AMLs) show a characteristic immunoreactivity with melanocyte differentiation markers such as monoclonal antibody (mAb) HMB45, which detects melanocyte differentiation antigen gp100 and mAb A103 reacting with Melan-A/MART-1. Monoclonal antibody T311 to tyrosinase (a key enzyme of melanogenesis) and mAb D5 to the microphthalmia (Mitf) antigen are two newly available markers of melanocytic differentiation. The authors tested 15 AMLs with T311 and D5 by immunohistochemistry and a subset of 3 cases by reverse transcription-polymerase chain reaction for their expression of tyrosinase and Mitf mRNA. T311 showed poor sensitivity in AMLs because only focal staining was seen in 1 out of 15 cases, although tyrosinase mRNA was found in all tested cases. Mitf mRNA was present in 3 of 3 tested cases, and D5 was positive in 15 of 15 AMLs. However, D5 immunostaining often was focal and not as homogeneous as A103, which was analyzed in a previous study. D5 staining also could be seen in other cell types such as normal renal tubular cells, macrophages, and renal cell carcinoma. The current results show that in contrast with HMB45 and A103, T311 has little or no value in the diagnosis of AMLs. D5 may be useful in a panel of antibodies in the diagnosis of AMLs.
Appl Immunohistochem Mol Morphol 2001 Mar
PMID:Immunohistochemical and reverse transcription-polymerase chain reaction expression analysis of tyrosinase and microphthalmia-associated transcription factor in angiomyolipomas. 1127 11


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