Journal of cellular physiology
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The platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase, implicated in the development and progression of different tumors, including gliomas. Chemoresistance is a common feature of malignant gliomas. Since receptor tyrosine kinases contribute to chemoresistance in tumors, we addressed whether PDGFR signaling might confer selective growth advantage to chemoresistant cells. ⋯ Cotreatment with inhibitors of phosphatidylinositol 3'-kinase (PI3K) or mitogen-activated protein kinase kinase (MEK) resulted in enhanced growth inhibition in glioma cells. Our results suggest that increased PDGF-BB signaling may sensitize chemoresistant glioma cells to STI571, suggesting a therapeutic potential for STI571 in patients with malignant gliomas refractory to chemotherapy. Simultaneous blockade of PDGFR and PI3K or Erk pathway may enhance therapeutic targeting in gliomas.
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Comparative Study
Developmental maturation of intestinal and renal thiamin uptake: studies in wild-type and transgenic mice carrying human THTR-1 and 2 promoters.
Thiamin (B1) is an essential micronutrient for normal growth and development. Mammals obtain thiamin through intestinal absorption, while in the kidney thiamin is reabsorbed to prevent its loss in the urine, both processes are specialized, carrier-mediated and involve thiamin transporters-1 and 2 (THTR-1 and THTR-2, respectively; products of the SLC19A2 and SLC19A3 genes). Although thiamin appears to play an important role in neonatal growth, little is currently known about the possible regulation of intestinal and renal thiamin uptake during developmental maturation. ⋯ We utilized wild-type mice (mice express orthologues of both thiamin transporters) and transgenic mice expressing human SLC19A2 or SLC19A3 promoter-reporter transgenes as a model system and examined carrier-mediated thiamin uptake, mTHTR-1 and 2 protein and mRNA levels and luciferase activity in suckling (13 days), weanling (25-27 days), and adult (60-65 days) mice. Carrier-mediated thiamin uptake by jejunal and renal brush border membrane vesicles (BBMV) both decreased with maturation (suckling>weanling>adult) and were associated with a reduction in mTHTR-1 and mTHTR-2 protein, mRNA levels, and the activity of human SLC19A2 and SLC19A3 promoter-reporter constructs in the intestines and kidneys of transgenic mice. These results are the first to demonstrate that intestinal and renal thiamin uptake are developmentally regulated during early stages of life, mediated through mTHTR-1 and mTHTR-2, and suggest the possible involvement of transcriptional regulatory mechanism(s) in this regulation.
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Imatinib mesylate is a tyrosine kinase inhibitor of the ABL, platelet-derived growth factor receptor (PDGFR), and c-kit kinases. Inhibition of BCR-ABL and c-kit accounts for its clinical activity in leukemia and sarcoma, respectively. In this report, we describe other cellular targets for imatinib. ⋯ Together, these results suggested that imatinib affects EGFR activation and signaling pathways through rapid release and increased expression of endogenous EGFR-activating ligands. Although, imatinib primarily inhibits tyrosine kinases, it also stimulates the activity of EGFR tyrosine kinase in head and neck squamous tumors. This finding demonstrates the need for careful use of this drug in cancer patients.
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Laminin, an extracellular matrix molecule, is known to promote neurite growth. In the present study, the effects of soluble laminin on organelle transport and their relation to neurite growth were investigated in cultured dissociated mouse dorsal root ganglion (DRG) neurons. Laminin added into the extracellular medium was deposited on the surface of DRG neurons. ⋯ In these growth cones, organelles protruded into nascent branches. In branches, soluble laminin increased organelle movement in the growth cone and the distal portion of the shaft. These results suggest that laminin inhibits the elongation of primary neurites but promotes branching and elongation of branches, all of which seem to be closely related to organelle transport.
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Topical intranasal application of the antifungal Amphotericin B (AmphoB) has been shown as an effective medical treatment of chronic rhinosinusitis. Because this antibiotic forms channels in lipid membranes, we considered the possibility that it affects the properties and/or cell surface expression of ion channels/pumps, and consequently transepithelial ion transport. Human nasal epithelial cells were exposed apically to AmphoB (50 microM) for 4 h, 5 days (4 h daily), and 4 weeks (4 h daily, 5 days weekly) and allowed to recover for 18-48 h. ⋯ After a 4-week treatment, a decrease in basolateral K(+) conductance and in alphaENaC and alpha1-Na(+)K(+)-ATPase mRNA levels was also observed. These findings may reflect a feedback mechanism aimed to limit cellular Na(+) overload and K(+) depletion subsequently to formation of AmphoB pores in the cell membrane. Thus, the decreased Na(+) absorption induced by AmphoB resulted from reduced cell surface expression of the ENaC, Na(+)K(+)-ATPase pump and NKCC1 and not from direct inhibition of their activities.