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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expression of a major cellular substrate for protein kinase C, the MARCKS protein, is regulated in a cell-, tissue-, and developmental stage-specific fashion; in addition, this expression can be stimulated acutely by various cytokines in certain cell types. We have begun to characterize the human gene in order to elucidate the genetic elements responsible for this highly regulated expression. We first cloned a human MARCKS cDNA, which encoded a predicted protein of 332 amino acids (Mr 31,600) that was approximately 89, 74, and 59% identical to the bovine, mouse, and chicken proteins, respectively. Regions conserved at the amino acid level included the amino-terminal myristoylation consensus sequence, the site of intron splicing, and the phosphorylation site domain. The human cDNA was used to demonstrate that tumor necrosis factor-alpha could rapidly stimulate MARCKS gene transcription in the human promyelocytic leukemia cell line HL60. Genomic clones were then isolated; sequence analysis identified a putative promoter region that had no TATA box and contained multiple transcription initiation sites in a region spanning 57 base pairs (bp). This was followed by a 5'-untranslated region of approximately 400 bp, which displayed a complex predicted secondary structure with a delta G of -73.4 kcal/mol. Plasmid constructions containing between 52 and 1453 bp of the human MARCKS promoter linked to the human growth hormone gene were then used in transient expression experiments. Constructions containing 52 and 110 bp of the MARCKS promoter did not exhibit promoter function while the larger constructions all exhibited promotor function; the 248-bp fragment of the MARCKS promoter was 80% as effective as the human ferritin promoter in stimulating expression of human growth hormone in intact cells. Using an insert from the human genomic clone as a probe, we identified human chromosome 6, q21-qter, as the location of the MARCKS gene; this has been assigned the gene symbol MACS.
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PMID:The human myristoylated alanine-rich C kinase substrate (MARCKS) gene (MACS). Analysis of its gene product, promoter, and chromosomal localization. 186 Aug 46

Iron-transferrin (FeTF) is an essential growth factor required for proliferation of lymphoid cells. FeTF activates protein kinase C (PKC) in the lymphoblastoid T-cell line, CCRF-CEM. We have treated CEM cells with human FeTF, then examined levels of PKC mRNA by hybridization analysis using cDNA probes specific for alpha-, beta-, and gamma-PKC subspecies. CEM cell mRNA hybridized with the beta-subspecies probe but not with probes for alpha- or gamma-subspecies. After exposure to FeTF an increase in PKC-beta mRNA was detectable at 10 minutes, peaked at 12 hours, and was sustained for 72 hours. Nuclear transcription assays demonstrated that rates of PKC-beta mRNA transcription were increased in FeTF-treated cells. By contrast, steady state levels of PKC-beta mRNA did not increase after treatment of cells with apotransferrin or gallium TF. Similarly, treatment with soluble iron as ferric ammonium citrate did not increase steady state levels of PKC-beta mRNA, despite producing a marked increase in cellular ferritin content. Ferritin increased from a baseline value of 63 ng/10(6) cells to 98 and 100 ng/10(6) cells in CEM cells treated for 1 hour with ferric ammonium citrate or FeTF, respectively. FeTF did not increase cytoplasmic-free calcium in CEM cells loaded with fura-2, indicating that binding of FeTF to transferrin receptors did not open membrane Ca2+ channels or release intracellular Ca2+. In addition, pretreatment of cells with desferrioxamine, but not ferrioxamine, blocked the FeTF-induced increase in PKC-beta transcripts. Therefore, iron as FeTF (not soluble iron or nonferric TF) stimulates transcription of the CEM cell PKC-beta gene. Transcriptional rate of the PKC-beta gene does not correlate with cellular iron content as judged by ferritin measurements. Furthermore, the requirement for FeTF does not appear to reflect activation of a classic agonist pathway as judged by stable cellular Ca2+. These data suggest that delivery of iron by FeTF to one or more specific cellular compartments may stimulate PKC-beta gene transcription in CEM cells.
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PMID:Induction of protein kinase C mRNA in cultured lymphoblastoid T cells by iron-transferrin but not by soluble iron. 200 52

Promastigotes and amastigotes of Leishmania mexicana amazonensis, incubated in the presence of 20 ng/ml of 12-O-tetradecanoyl phorbol-13-acetate (TPA), an exogenous protein kinase C activator, developed several membrane and cytoplasmic alterations. Increased exocytic activity was observed especially in the amastigotes which had an enlarged flagellar pocket. Treatment with TPA induced protrusions of the plasma membrane where cytoplasmic elements (ribosomes and sub-pellicular microtubules) were not seen. Freeze-fracture replicas of TPA-treated parasites showed reduction in the density of the intramembranous particles (IMP), which were not seen on either fracture face of the membrane lining the protrusion. Cytochemical observations showed that sterols and anionic sites which bind to filipin and cationized ferritin particles, respectively, can be detected in the membrane lining the protrusions. However, the pattern of distribution of anionic sites, which bind colloidal iron hydroxide particles, and acid phosphatase in the membrane lining the protrusion region differed from the other portions of the plasma membrane.
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PMID:Effects of phorbol ester on Leishmania mexicana amazonensis: an ultrastructural and cytochemical study. 317 96

Transferrin receptors have been previously found on human macrophages and it has also been shown that transferrin iron is taken up by these cells. It has therefore been inferred that the uptake is receptor mediated and involves an endocytic pathway. The subject was addressed directly in the present study in which the transferrin-iron-receptor interaction was characterized in cultured human blood monocytes. Specific, saturable diferric transferrin binding was demonstrated, with a kDa of 3.6 X 10(-8) M and a calculated receptor density of 1.25-2.5 X 10(5) receptors per cell. Incubation at 4 degrees C markedly reduced transferrin binding and completely inhibited iron uptake. Chase experiments confirmed progressive cellular loading of iron, with concomitant loss of transferrin. Inhibitors of endocytic vesicle acidification (ammonium chloride and 2,4-dinitrophenol) inhibited iron unloading from endocytosed diferric transferrin, while microtubular inhibitors (colchicine and vindesine) and a microfilament inhibitor (cytochalasin B) reduced diferric transferrin uptake but had little effect on the iron unloading pathway. A similar effect was noted with a calcium ion antagonist (verapamil) and with 2 calmodulin antagonists (chlorpromazine and imipramine). These latter findings suggest the importance of cytoskeleton-membrane interactions via a calcium, calmodulin and protein kinase C mediated system. Endocytosed iron accumulated progressively as ferritin within the cultured monocytes.
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PMID:Transferrin receptors and transferrin iron uptake by cultured human blood monocytes. 362 25

The expression of thyroglobulin and other thyroid-specific markers depends upon the activation of protein kinase A (PKA) by cyclic AMP. A rat thyroid cell line dedifferentiates when transformed with Ki-ras oncogene. The decrease in thyroglobulin gene expression parallels a reduction in the level of PKA nuclear catalytic subunit. We find that the activity of cAMP-responsive elements and thyroglobulin promoters is down-regulated in Ras-transformed cells. Transcription of a third cAMP-regulated gene, H-ferritin, is similarly reduced. cAMP-responsive element and H-ferritin expression were stimulated when intracellular cAMP levels were increased. Reactivation of the thyroglobulin promoter required depletion of PKC in addition to increased cAMP. We also find that v-Ras activation leads to a significant increase in membrane-bound PKC. These data support the idea that v-Ras via PKC inhibits the transmission of cAMP-PKA signals to the nucleus. We suggest that the thyroglobulin promoter is more sensitive than other cAMP-dependent promoters to reduced nuclear levels of PKA catalytic subunit.
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PMID:Ki-ras oncogene interferes with the expression of cyclic AMP-dependent promoters. 771 89

The iron-responsive element-binding protein (IRE-BP) is a cytosolic RNA-binding protein that functions in the maintenance of iron homeostasis by post-transcriptionally regulating transferrin receptor and ferritin synthesis. Little is known concerning how factors other than iron may modulate the activity of this central regulator of cellular iron utilization. We present evidence indicating that phosphorylation of the IRE-BP by protein kinase C (PKC) could provide a mechanism for regulation of IRE-BP function. Purified rat liver IRE-BP was phosphorylated by PKC up to 1.3 mol of phosphate/mol of protein with Ser the modified amino acid. Ser was also the phosphoacceptor in the IRE-BP in intact cells. The Km of PKC for the IRE-BP was 0.4 microM. Tryptic phosphopeptide mapping identified one major phosphopeptide plus several other peptides with lesser amounts of phosphate. Synthetic peptides of the IRE-BP containing Ser 138 (site A) and Ser 711 (site B) were phosphorylated by PKC. In HL 60 cells, addition of phorbol 12-myristate 13-acetate (PMA) stimulated IRE-BP phosphorylation within 30 min and increased high affinity IRE RNA binding activity 2-fold. After 90 min, the level of phosphorylation had increased further, and high affinity IRE RNA binding activity had increased 3-fold above the control. Incorporation of [35S]Met into immunoprecipitable IRE-BP was not altered in cells treated with PMA for 30 or 90 min. PMA also stimulated IRE-BP phosphorylation in rat fibroblasts. Taken together, our studies begin to define a novel mechanism by which hormones, growth factors, and other agents may regulate cellular iron utilization through specific phosphoregulation of the IRE-BP.
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PMID:Iron-responsive element-binding protein. Phosphorylation by protein kinase C. 826 77

Iron regulatory proteins (IRPs) are RNA-binding proteins that post-transcriptionally regulate synthesis of iron uptake (transferrin receptor) and storage (ferritin) proteins. Our previous work demonstrating that IRP1 is phosphorylated by protein kinase C supported the hypothesis that factors in addition to iron modulate IRP function. We have investigated changes in activity and expression of both IRP1 and IRP2 during phorbol 12-myristate 13-acetate (PMA)-induced differentiation of HL-60 cells. In contrast to IRP1, IRP2 was highly phosphorylated in untreated cells. PMA stimulated phosphorylation of IRP1 and IRP2 by at least 2-3-fold without affecting incorporation of [35S]methionine into the proteins. IRP1 and IRP2 isolated from PMA-treated cells displayed different phosphopeptides. Phosphorylation of IRPs was associated with a 2-fold increase in high affinity RNA binding activity without altering KD, and this was accompanied by a 50% increase in transferrin receptor mRNA abundance. PMA acted on a latent pool of binding activity that is present in a nonaconitase oxidized form and is largely composed of a stable but inactive species of IRP2. Desferal and hemin modulated iron-responsive element binding activity in HL-60 cells without affecting the phosphorylation state of IRP1. Hemin appeared to reduce the abundance of phosphorylated IRP2. Thus, multiple factors affect the function of both IRPs and indicate that extracellular agents may program changes in cellular iron metabolism by altering the phosphorylation state of these regulatory RNA-binding proteins.
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PMID:Phosphorylation and activation of both iron regulatory proteins 1 and 2 in HL-60 cells. 863 54

The mRNA coding for H-ferritin was highly induced in human monocytic THP-1 cells following treatment with phorbol 12-myristate 13-acetate (PMA). The induction was detected at 3 h, reached maximal levels at 12 h, and was sustained for up to 48 h subsequent to PMA exposure. PMA-induced up-regulation of H-ferritin gene expression was also observed in other leukaemic cell lines, HL60 and U937, but not in non-leukaemic cell types, including human fibroblasts, endothelial cells and smooth muscle cells. The effect of PMA could be completely blocked by the protein kinase C inhibitor, H-7. Furthermore, treatment of THP-1 cells with bacterial phospholipase C also produced a marked increase in expression of H-ferritin mRNA, suggesting the activation of protein kinase C was responsible for the accumulation of mRNA. Nuclear run-off experiments demonstrated that PMA did not increase the transcriptional rate of the H-ferritin gene. In contrast, the half-life of the H-ferritin mRNA measured in the presence of actinomycin D was greatly prolonged in PMA-treated cells. The induction of H-ferritin mRNA by PMA required no protein synthesis. Conversely, treatment of THP-J cells with protein synthesis inhibitor, cycloheximide, resulted in a 4-5-fold increase in H-ferritin mRNA. The increase in the stability of the H-ferritin mRNA was also observed in cells treated with cycloheximide. Taken together, these results suggest that the stability of H-ferritin mRNA in THP-1 is subjected to regulation via a protein kinase C-mediated phosphorylation on existing putative protein factor(s).
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PMID:Post-transcriptional regulation of H-ferritin gene expression in human monocytic THP-1 cells by protein kinase C. 887 Jun 67

Available evidence suggests that glucose, the most potent physiologic insulin secretagogue, capacitates glucose-induced insulin secretion by stimulating synthesis of various proteins in the beta cell. To obtain more clues about proteins that might be involved in insulin secretion, rat pancreatic cDNA libraries were screened by differential hybridization for non-preproinsulin transcripts that were increased when pancreatic islets were cultured for 1 day at a high (20 mM) versus a low concentration (1 mM) of glucose. More than 100,000 pfu were initially screened. After repeated rescreening, 33 transcripts were 1-3-fold higher in the presence of the high glucose. For comparison, preproinsulin transcripts were 4-8-fold higher at the high concentration of glucose. The sequences of 12 clones were > or = 85% similar to published sequences. These included annexin, calbindin, protein kinase C receptor, the G protein beta subunit, the guanyl cyclase A/atrial natriuretic peptide receptor and the serotonin 5HT-2 receptor. As previously reported, ferritin H chain transcripts were discovered to be 3-6-fold higher in the presence of the high glucose (MacDonald et al., FASEB J. 8, 777-781, 1994). Unidentified glucose responsive clones have been assigned GenBank accession numbers N55606-N55636, N65938 and N65939. The results implicate the proteins encoded by these mRNAs in insulin secretion.
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PMID:Glucose-stimulated expressed sequence tags from rat pancreatic islets. 896 Dec 57

By observing increases in the transepithelial paracellular permeability of a range of radiolabeled solutes and electron dense dyes, changes in molecular sieving caused by the cytokine, TNF (tumor necrosis factor), and the phorbol ester, TPA (12-0-tetra-decanoylphorbol-13-acetate), were characterized. Using 14C-labeled mannitol (mw 182), raffinose (mw 504), PEG (polyethylene glycol; mw 4000), and dextran (mw 10,000, 70,000 and 2,000,000), the transepithelial flux rates of these compounds were determined at the peak of the transepithelial electrical resistance (TER) changes caused by these two agents. TNF treatment resulted in increased permeability across LLC-PK1 epithelial cell sheets only to relatively small solutes, with an upper limit of approximately 4,000 mw. The low molecular weight "ceiling" for the TNF-treated epithelium is further evidence against TNF increasing transepithelial permeability by means of inducing nonspecific, microscopic "holes" in the epithelium, for which a "ceiling" would not exist. TPA treatment increases transepithelial paracellular permeability to a much broader range of solutes, extending well beyond 2 million mw. Transmission electron micrographs provide evidence that even the electron-dense dye complex, ruthenium red, can cross tight junctions of TPA-treated cell sheets. However, cationic ferritin cannot cross tight junctions of TPA-treated cell sheets. This shows that there is an upper limit to solutes able to cross TPA-treated cell sheets, but that this upper limit will include most proteins, which would then be able to cross tumor promoter-exposed (protein kinase C-activated) epithelial layers at accelerated rates. The biomedical implications for a high molecular weight cutoff in tumor promoter action in epithelial carcinogenesis, and for a low molecular weight cutoff in cytokine-induced epithelial apoptosis in inflammation, are discussed.
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PMID:Different size limitations for increased transepithelial paracellular solute flux across phorbol ester and tumor necrosis factor-treated epithelial cell sheets. 913 Apr 71


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