PubMed · 7741940
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J I Epstein. 1995. Malpractice vs benepractice.. https://pubmed.ncbi.nlm.nih.gov/7741940/
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The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.
Cytotoxic effects of the Annonaceous acetogenin, bullatacin, were studied in multidrug-resistant (MDR) human mammary adenocarcinoma (MCF-7/Adr) cells vs. the parental non-resistant wild type (MCF-7/wt) cells. Bullatacin was effectively cytotoxic to the MCF-7/Adr cells while it was more cytostatic to the MCF-7/wt cells. ATP depletion is the mode of action of the Annonaceous acetogenins, and these agents offer a special advantage in the chemotherapeutic treatment of MDR tumors that have ATP-dependent mechanisms.
This paper describes the biosynthesis of L-CanAg, a mucin-like glycoprotein which carries the carcinoma-associated carbohydrate epitope sialyl-Lewis a and is secreted by the colon adenocarcinoma cell line COLO 205. Recently, it has been shown that L-CanAg is a novel glycoform of CD43, a surface sialoglycoprotein normally found only on hematopoietic cells. Immunoprecipitation with alpha-GPEP18, a novel antiserum against the cytoplasmic domain of CD43, detected a transmembrane form of L-CanAg carrying sialyl-Lewis a. Cell surface biotinylation experiments demonstrated the presence of transmembrane L-CanAg at the plasma membrane and that COLO 205, unlike the leukocyte cell line HL-60, contained significant amounts of glycosylated intracellular CD43. Immunoprecipitation of phosphate-labeled COLO 205 cells revealed that membrane-bound L-CanAg, like leukocyte CD43, is a phosphoprotein. Interestingly, both surface- and phosphate-labeled L-CanAg were eluted earlier from a gel filtration column than their unlabeled counterparts, indicating that this method could separate membrane-bound L-CanAg from its soluble form. Immunoprecipitations of pulse-chase-labeled COLO 205 lysates fractionated by gel filtration showed that decrease in membrane-bound L-CanAg was concomitant with an increase in the intracellular soluble form. Together, these data indicate that transmembrane L-CanAg is fully glycosylated and phosphorylated before the extracellular domain is cleaved off and stored inside the cell before exocytosis.