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  • 1
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 660 (1992), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Nutrition 24 (2004), S. 201-221 
    ISSN: 0199-9885
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Studies utilizing experimental animals, epidemiological approaches, cellular models, and clinical trials all provide evidence that retinoic acid and some of its synthetic derivatives (retinoids) are useful pharmacological agents in cancer therapy and prevention. In this chapter, we first review the current knowledge of retinoic acid receptors (RARs) and their role in mediating the actions of retinoic acid. We then focus on a discussion of RARalpha and acute promyelocytic leukemia followed by a discussion of the role of RARs, in particular RARbeta expression, in other cancer types. Loss of normal RAR function in the presence of physiological levels of RA (either due to alterations in the protein structure or level of expression) is associated with a variety of different cancers. In some cases treatment with pharmacological doses of RA can be effective.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1327
    Keywords: Key words Arginase ; Manganoenzymes ; Catalase ; Peroxidase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract  Rat liver arginase contains a dinuclear Mn2(II,II) center in each subunit having EPR properties similar to those observed in Mn-catalases. The principal physiologic role of arginase is catalyzing the hydrolytic cleavage of l-arginine to produce l-ornithine and urea. Here we demonstrate that arginase catalyzes the disproportionation of hydrogen peroxide by a redox mechanism analogous to Mn-catalases, but at rates that are 10–5 to 10–6 of k cat for the Mn-catalases, and also exhibits peroxidase activity. The dinuclear Mn2(II,II) center is essential for maximal catalase activity, since both the H101N and H126N mutant arginases containing only one Mn(II)/subunit have catalase activities that are 〈3% of that for the wild-type enzyme. Like the Mn-catalases, the catalase activity of arginase is not inhibited by millimolar concentrations of CN–, the most potent inhibitor of heme catalases, or by EDTA, a chelator of free metal ions. The catalase activity of arginase is not significantly inhibited by Cl– or F–, in contrast to Mn-catalases, while potent inhibitors of the hydrolytic activity are also effective inhibitors of the catalase activity. These results suggest that lower affinity of hydrogen peroxide to the active site of arginase contributes to the lower catalase activity. EPR spectroscopy reveals that potent inhibitors of the hydrolytic reaction, including N ω-hydroxy-l-arginine, l-lysine, and l-valine, decouple the electronic interaction between the Mn2+ ions, most probably by removing a μ-bridging ligand or by increasing the intermanganese separation. The capacity for arginase to deliver a hydroxide ion to hydrolyze the l-arginine substrate is suggested to arise from a "dinuclear effect", wherein the two metal ions contribute more or less equivalently in deprotonation of metal-bound water molecule. Structure-reactivity analyses of these reactions will provide insights into the factors that control redox versus hydrolytic function in dimanganese clusters.
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Molecular and cellular biochemistry 75 (1987), S. 61-70 
    ISSN: 1573-4919
    Keywords: gene expression ; development ; tissue-specific expression ; cell cycle-dependent genes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract 4F1, 2A9 and 2F1 represent three of a number of cDNA sequences which have been identified because their cognate RNAs markedly increase when quiescent cells in culture are stimulated with serum. Studies using a variety of cell culture systems have shown that the expression of these genes is modulated by various growth factors and mitogens and thus such genes are considered to be ‘growth-associated.’ Thus far, little information has been obtained with these in vitro systems about the function of these genes. In an attempt to begin to elucidate the role of these genes (if any) in the physiology of the normal cell, we have analyzed the levels of 4F1, 2A9 and 2F1 transcripts in a variety of differentiated organs and tissues of adult and fetal rats. Our results show that each of these growth-associated genes exhibits its own unique pattern of expression, unrelated to the proliferative activity of the tissue. These data suggest that these genes most likely do have specific functions in normal tissue in addition to their role in the induction of DNA synthesis in quiescent cells in culture.
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  • 6
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: WI-38 cells, density arrested for short periods of time, can be stimulated to re-enter the cell cycle by epidermal growth factor (EGF) alone. However, cells density arrested for longer periods have a prolonged prereplicative phase when serum stimulated and cannot be stimulated by EGF alone. Radio-ligand binding studies performed on WI-38 cells showed that actively growing cells bind [125I]EGF at relatively low levels that increase to a maximum as the cells become contact inhibited. As the cells enter a state of deeper quiescence, EGF binding falls to one-third to one-fifth the short-term growth arrested levels, remaining constant thereafter. The EGF-receptor complexes internalize more slowly in long-term growth arrested cells, and the rate of ligand association to the receptor is lower than short-term growth arrested cells. The amount of EGF receptor protein in lysates of equal numbers of both short- and long-term quiescent cells remains the same. These results suggest that the failure of long-term growth arrested cells to respond to EGF is not due to dramatic changes in the amount of receptor protein during prolonged quiescence but more likely to an alteration in the ability of these receptors to bind ligand and/or activate the EGF signal transduction pathway. © 1993 Wiley-Liss, Inc.
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  • 7
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: Analysis of gene expression following stimulation of growth-arrested cells has beei the main approach for identification of growth-associated genes. Since the activation of these gene sequences is dependent on both the stimulatory agent and theitate of quiescence of the cell, the activation and role of the same genes may be entirely different in non-growth arrested, actively proliferating cells. We have addressed the question of growth-associated gene expression during active growth by analyzing gene expression during G-1 of cells which have jusl exited mitosis without first leaving the cell cycle. We were able to isolate, by a non-inductive, drug free system, a population of highly synchronized Swiss 3T3 cells within mitos is (〉90%) in numbers sufficient to determine the pattern of expression pf a large number of representative growth-associated genes. Our results show that after replating the mitotic ceils into conditioned medium: (1) growth-associated gene expression is not constant during G-1 of actively proliferating cells, and (2) while a number of genes (e.g., JE, c-myc, ODC, p53, and histone) exhibited patterns of expression similar to that reported in the quiescent systems, others (e.g., nur-77, vimentin, calcyclin) exhibited patterns which were completely different. From these results, we can begin to construct a temporal map of G-1 progression during active growth.
    Additional Material: 6 Ill.
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  • 8
    ISSN: 0021-9541
    Keywords: Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Medicine
    Notes: WI-38 cells can remain quiescent for long periods of time and still be induced to reenter the cell cycle by the addition of fresh serum. However, the longer these cells remain growth arrested, the more time they require to enter S phase. This prolongation of the prereplicative phase has been localized to a point early in G1, after the induction of “immediate early” G1 genes such as c-fos and c-jun but before maximal expression of “early” G1 genes such as ornithine decarboxylase (ODC). Understanding the molecular basis for ODC mRNA induction can therefore provide information about the molecular events which regulate the progression of cells out of long-term quiescence into G1 and subsequently into DNA synthesis. Studies utilizing electrophoretic mobility shift assays (EMSA) of nuclear extracts from short- and long-term quiescent WI-38 cells identified a region of the human ODC promoter at -491 bp to -474 bp which exhibited a protein binding pattern that correlated with the temporal pattern of ODC mRNA expression. The presence of a CACGTG element within this fragment, studies with antibodies against c-Myc and Max, the use of purified recombinant c-Myc protein in the mobility shift assay, and antisense studies suggest that these proteins can specifically bind this portion of the human ODC promoter in a manner consistent with growth-associated modulation of the expression of ODC and other early G1 genes following prolonged quiescence. These studies suggest a role for the c-Myc/Max protein complex in regulating events involved in the progression of cells out of long-term quiescence into G1 and subsequently into S. © 1995 Wiley-Liss, Inc.
    Additional Material: 8 Ill.
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  • 9
    Electronic Resource
    Electronic Resource
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 59 (1995), S. 42-52 
    ISSN: 0730-2312
    Keywords: WI-38 cells ; protein tyrosine kinases ; IGF-1 receptor ; growth factors ; EGF ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: We have used the WI-38 cell long-term quiescent model system to study the regulation of cell cycle progression at the molecular level. By modulating the length of time that WI-38 cells are density arrested, it is possible to proportionately alter the length of the prereplicative or G-1 phase which the cell traverses after growth factor stimulation in preparation for entry into DNA synthesis. Stimulation of long-and short-term density arrested WI-38 cells with different growth factors or higher concentrations of individual growth factors does not alter the time required by long-term cells to enter S after stimulation. However, the time during the prereplicative period for which these growth factors are needed is different. Long-term quiescent WI-38 cells require EGF to traverse the G-0/G-1 border but do not need and apparently cannot respond to IGF-1 during the first 10 h after EGF stimulation, the length of the prolongation of the prereplicative phase. This suggests that EGF stimulation of long-term quiescent WI-38 cells initiates a series of molecular events which make these cells “competent” to respond to the “progression” growth factor, IGF-1. In light of the well-established role of protein tyrosine kinases in signal transduction, we set out to identify, clone, and analyze the expression of receptor and non-receptor tyrosine kinases which potentially could play a role during the prolongation of the prereplicative phase in making the long-term quiescent WI-38 cells competent to respond to IGF-1. We obtained 49 clones representing 11 different receptor and non-receptor type protein tyrosine kinases. Analysis of expression of these clones revealed a variety of different patterns of expression. However, the most striking pattern was exhibited by IGF-1 receptor. Our results suggest that induction of IGF-1 receptor mRNA by EGF may be an important event in the establishment of competence by EGF in long-term density arrested WI-38 cells. © 1995 Wiley-Liss, Inc.
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  • 10
    Electronic Resource
    Electronic Resource
    New York, N.Y. : Wiley-Blackwell
    Journal of Cellular Biochemistry 55 (1994), S. 503-512 
    ISSN: 0730-2312
    Keywords: cell cycle ; immediate-early competence genes ; antisense ; mitotic selection ; Swiss 3T3 cells ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: The proto-oncogenes c-fos and c-jun have been shown in numerous model systems to be induced within minutes of growth factor stimulation, during the G0/G1 transition. In this report we use the mitotic shake-off procedure to generate a population of highly synchronized Swiss 3T3 cells. We show that both of these immediate-early, competence genes are also induced during the M/G1 transition, immediately after completion of mitosis. While c-fos mRNA levels drop to undetectable levels within 2 hr after division, c-jun mRNA levels are maintained at a basal level which is ∼ 30% maximum throughout the remainder of G1. In order to access the functional significance of these patterns of c-fos and c-jun expression, antisense oligodeoxynucleotides specific to c-fos or c-jun were added to either actively growing Swiss 3T3 cells or mitotically synchronized cells, and their ability to inhibit DNA synthesis and cell division determined. Our results show that treatment of Swiss 3T3 cells with either c-fos or c-jun antisense oligodeoxynucleotides, while actively growing, during mitosis, or in early G1, results in a reduction in ability to enter S and subsequently divide. This was also true if Swiss 3T3 cells were treated during mid-G1 with c-jun antisense oligodeoxynucleotides. These results demonstrate that the regulation of G1 progression following mitosis is dependent upon the expression and function of the immediate-early, competence proto-oncogenes c-fos and c-jun. © 1994 Wiley-Liss, Inc.
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