Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20645 (mannose-6-phosphate receptor)
 320 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methotrexate (MTX) covalently linked to poly(L-lysine) [poly(Lys)] enters cells by endocytosis, is degraded in lysosomes and, upon liberation of small molecular methotrexate, is cytocidal to Chinese hamster cells in culture. This drug conjugate was used to select mutants resistant to MTX-poly(Lys), which were examined for defects in endocytosis. Two mutants resistant to MYX-poly(Lys) and sensitive to free MTX, MPL 3-4 and MPL 2-5, internalized the conjugate in normal fashion, but had a decreased ability to degrade it to small molecular drug. The magnitude of this defect in the two mutants correlated with their level of resistance. In addition, both mutants were cross resistant to diphtheria toxin and modeccin and hypersensitive to ricin. While MPL 3-4 internalized MTX-poly(Lys) and inulin normally, it showed decreased endocytosis via the mannose-6-phosphate receptor and decreased uptake of 125I-alpha-2 macroglobulin. Acidification of subcellular fractions was measured using the partitioning of acridine orange. In MPL 3-4, the ATP-driven acidification of the endosome-containing cell fractions was slightly decreased (80% of controls), while acidification of the heavy lysosome-containing fraction was normal. Complementation analysis using hybrids of MPL 3-4 x MPL 2-5 indicated that the mutations occurred at the same gene, but were expressed with different severity. This genotype is identical to that of the End 2 mutants described by Roff et al. (1986). Thus, surprisingly, mutants with identical genotypes were isolated independently by totally different selection procedures.
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PMID:Methotrexate-poly(lysine) as a selective agent for mutants of Chinese hamster ovary cells defective in endocytosis. 337 97

In vitro human natural cell-mediated cytotoxicity (NCMC) to K-562, Molt-4, and F-265 cells is inhibited in a dose-dependent manner by mannose 6-phosphate, fructose 1-phosphate and fructose 6-phosphate. This inhibition is not observed with mannose, glucose, fucose, glucose 6-phosphate, mannose 1-phosphate, galactose 1-phosphate, or galactose 6-phosphate. Preincubation of the effector cells, obtained from fresh whole blood, with mannose-6-phosphate, fructose-1-phosphate, or fructose-6-phosphate did not inhibit cytotoxicity, which indicated that these hexose phosphates are not nonspecifically toxic towards the effector lymphocytes. Mannose-6-phosphate and the stereochemically similar fructose-1-phosphate are more potent inhibitors than fructose-6-phosphate in terms of concentration required and time of onset of effect. Inhibition of cytotoxicity by mannose-6-phosphate varied with target cell type: F-265 is protected at much lower concentrations of mannose-6-phosphate (less than 1 mM) than is either Molt-4 or K-562. The inhibition of NCMC is also observed with the inhibitors of lysosomal function, NH4Cl, and chloroquine. The presence of a functional mannose-6-phosphate receptor on target cells was demonstrated: (i) Gelonin, a seed protein that inactivates the eukaryotic ribosome but is nontoxic to intact cells, was covalently linked to monophosphopentamannose, and this conjugate ws toxic to both K-562 and F-265 target cells, the latter being by far the more sensitive; and (ii) chloroquine, NH4Cl, and mannose-6-phosphate all inhibited the toxicity of gelonin-monophosphopentamannose. These results suggest either that a cytolytic lymphokine contains a hexose phosphate residue and may be taken up by target cells through the lysosomal/mannose 6-phosphate pathway or that such a residue is involved in target cell-effector cell recognition.
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PMID:Mannose 6-, fructose 1-, and fructose 6-phosphates inhibit human natural cell-mediated cytotoxicity. 694 16

Endocytosis and intracellular transport of ricin were studied in stable transfected HeLa cells where overexpression of wild-type (WT) or mutant dynamin is regulated by tetracycline. Overexpression of the temperature-sensitive mutant dynG273D at the nonpermissive temperature or the dynK44A mutant inhibits clathrin-dependent endocytosis (Damke, H., T. Baba, A.M. van der Blieck, and S.L. Schmid. 1995. J. Cell Biol. 131: 69-80; Damke, H., T. Baba, D.E. Warnock, and S.L. Schmid. 1994. J. Cell Biol. 127:915-934). Under these conditions, ricin was endocytosed at a normal level. Surprisingly, overexpression of both mutants made the cells less sensitive to ricin. Butyric acid and trichostatin A treatment enhanced dynamin overexpression and increased the difference in toxin sensitivity between cells with normal and mutant dynamin. Intoxication with ricin seems to require toxin transport to the Golgi apparatus (Sandirg, K., and B. van Deurs. 1996. Physiol. Rev. 76:949-966), and this process was monitored by measuring the incorporation of radioactive sulfate into a modified ricin molecule containing a tyrosine sulfation site. The sulfation of ricin was much greater in cells expressing dynWT than in cells expressing dynK44A. Ultrastructural analysis using a ricin-HRP conjugate confirmed that transport to the Golgi apparatus was severely inhibited in cells expressing dynK44A. In contrast, ricin transport to lysosomes as measured by degradation of 125I-ricin was essentially unchanged in cells expressing dynK44A. These data demonstrate that although ricin is internalized by clathrin-independent endocytosis in cells expressing mutant dynamin, there is a strong and apparently selective inhibition of ricin transport to the Golgi apparatus. Also, in cells with mutant dynamin, there is a redistribution of the mannose-6-phosphate receptor.
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PMID:Expression of mutant dynamin inhibits toxicity and transport of endocytosed ricin to the Golgi apparatus. 945 16