Full Journal - Journal of Cell and Molecular Biology - Haliç Üniversitesi

More documents

Recommendations

Info

60 Mustafa Yatin regulation of cell growth depending on need. The polyamine requirement of a given cell may be covered by de novo synthesis or by uptake from its environment. Under physiologic conditions, the relative importance of uptake and de novo synthesis is a cell-typic character (Marton and Pegg, 1995; Seiler and Dezeure, 1990; Seiler et al., 1990). The capacity of cells for de novo synthesis and uptake is an expression of their ability to adapt to environmental changes. The use of polyamine levels in body fluids as diagnostic markers or as indices of novel therapeutic effects has also been subject to extensive study but the results have, with a few exceptions, been disappointing. The extreme complexity of blood compartment carrying free polyamines in the plasma caused significant problems in the clinical interpretation of circulating PA levels. By the end of 1970s the unclear potential role of PA as markers for cancer led to an almost total disinterest in their diagnostic use (Moulinoux et al., 1996). However, studies of polyamine metabolism in a number of pathogenic parasites (Seiler and Atanassov, 1994), inflammatory, infectious conditions (Yatin and Fischman, 2002) and under oxidative stress (Gilad and Gilad, 1999), have led to identification a number therapeutic targets and the development of novel chemotherapeutic agents (Pegg and McCann, 1994; Wallace and Morgan, 1990; Hebby, 1981; Seiler and Atanassov, 1994). Polyamines are also modulators of synaptic functions and play important roles in central nervous system (CNS) (Gilad and Gilad, 1999; Yatin et al., 2001; Williams, 1997). Some of the non-peptide venoms of spiders and wasps are natural polyamine analogues that are selective inhibitors of the glutamate receptors of the CNS (Nihei et al., 2001; Palma et al., 1998; Albensi et al., 2000). Many plant compounds contain polyamine residues, including several families of alkaloids (Hoet and Nemery, 2000; Thomas and Thomas, 2001). Resveratrol, a natural polyphenolic phytoalexine, present abundantly in red wine, has been reported to be an anti-proliferative agent on human cancer cells, also caused significant decreases on ODC activity, indicating that PA might represent one of several beneficiary effects of moderate consumption of red wine (Nigdigar et al., 1998; Scheneider et al., 2000). Spm, exceptionally high in skin (human skin concentration - epidermis is 850 mg/g tissue compared to muscle - skeletal, 30 mg/g tissue), has been identified as a potent antioxidant and anti-inflammatory agent against UVB irradiation and oxidative stress and suggested to be an important anti-inflammatory antioxidant of epidermis. Currently, the use of Spm as a dermatologic antioxidant is under patent protection (Lovaas, 1995). Biosynthesis and regulation of cellular polyamines The biosynthesis pathway of polyamine accumulation in the cells is kinetically rate-limited by ornithine decarboxylase (ODC; EC 4.1.1.17), a pyridoxal phosphate dependent enzyme, which synthesize Put by decarboxylation of L-ornithine. The remarkable elevation in de novo polyamine biosynthesis rate that takes place in rapidly growing cells has led to much effort to develop therapeutically useful antineoplastic agents that would interfere with, or regulate, these processes in hyperproliferative diseases (Seiler and Atanassov, 1998). Investigation of several specific inhibitors of ODC (i.e. difluoromethylornithine, DFMO, a suicidal irreversible specific inhibitor of ODC) as an experimental antineoplastic strategy causes to reduction in total amount of cellular polyamines (except spermine) with only cytostatic effects. The lack of cytotoxicity may be due to polyamine interconversion from a spermine reservoir in the cells and/or polyamine repletion by transmembrane uptake from extracellular sources (Pegg and McCann, 1994; Hebby, 1981; Seiler and Atanassov, 1998). Many microorganisms and higher plants are able to biosynthesize Put from agmatine produced by decarboxylation of arginine, however all mammalian cells and many lower eukaryotes lack arginine decarboxylase (ADC), leaving the only route to produce Put to utilize the ODC. Ornithine is available for this enzymatic reaction from the circulating plasma and can also be formed by the action of arginase. Arginase is much more widely distributed than any other enzymes of the urea cycle in living organisms and present in extrahepatic tissues, and ensures the availability of ornithine in PA production line. In a broad sense, arginase can, therefore be assumed of as an initial step in the PA biosynthesis pathway. Ornithine decarboxylase was discovered in 1968 simultaneously and independently in two laboratories in the United States and one in Finland (Janne et al.,
1991, Russel and Synder, 1968; Pegg and Williams, 1968). Ornithine decarboxylase is a unique enzyme in many respects. First, it is one of the enzymes having extremely short life with a very rapid turnover rate (t1/2 is from 10 to 20 minutes) and it is present in very small amounts in normal growing cells. Its activity can be increased many folds within a few hours of exposure to trophic stimuli (Janne et al., 1991). Such stimuli include hormones, various drugs, tissue regeneration and growth factors commonly found in serum. Even after such stimulation, ODC remains only a very small fraction of the total cellular protein ranging from 0.01% of the cytosolic protein in androgen - stimulated mouse kidneys to 0.00012 % in thioacetamide stimulated rat liver. It turned out that by any definition this enzyme is a low abundance Polyamines 61 Figure 2: Cellular PA pool is regulated by three influences: production, transport and catabolism. Antizyme has a negative feedback control on production and transport. Antizyme is a key factor in cellular PA homoestasis and its production depends on PA level. When cellular PA levels rise, +1 frame-shifting in AZ ribosomal mRNA occurs causing read-through of the internal stop codon to produce the full length antizyme protein. ODC is active and stable enzyme, if only, it forms a homodimer in trans form across the face of the active dimer. Higher affinity of AZ towards ODC, generates an AZ-ODC heterodimer exposing the C-terminus of ODC, which is then immediately recognized and degraded by the 26S proteosome. In contrast with all other cellular proteins degraded by this proteolytic pathway, the degradation of ODC is not triggered by ubiquitination. AZ also reversibly binds to some functional component of the cytoplasmic membrane PA uptake transporter and thereby preventing utilization of extracellular sources of PAs. AZ by itself can be bound by an AZ inhibitor, which is an ODC-like protein that does not posses ODC activity but which does bind AZ more strongly than the AZ-ODC complex, and so consequently sequesters the AZ protein. In this negative feedback loop; cellular PA rise to excessive amounts; PA induce more AZ; AZ inhibits and diminishes ODC and PA uptake; PA accumulation in cells decline. protein representing only about 3 ppm (part per million) of the soluble proteins of a mammalian cell. Second, treatment of cells with exogenously added polyamines cause negative feedback and result in a rapid and profound fall in enzymatic activity of ODC. Cannelakis (1989) found that the loss of ODC activity coincided with the appearance of another enzyme activity that was inhibitor of ODC. This activity was called anti-enzyme for ODC or more briefly antizyme (Coffino, 2001; Heller et al., 1976). The low abundance of both proteins presented tremendous challenge in studying their isolation and biochemical nature, physiological behavior and chemical mechanism of their interaction. Shin-Ichi Hayashi, addressed the problem by purifying ODC to homogeneity, a very difficult task at that time, to
Page 1 and 2: STANBUL 1998 VOLUME 1 • NO. 2 •
Page 3 and 4: Journal of Cell and Molecular Biolo
Page 5 and 6: 46 Gülriz Bayçu Cd Contamination
Page 7 and 8: 48 Gülriz Bayçu Figure 2: Optimiz
Page 9 and 10: 50 Gülriz Bayçu PC production was
Page 11 and 12: 52 Gülriz Bayçu plants and fungi
Page 13 and 14: 54 Gülriz Bayçu References Abraha
Page 17: cells (cancer), inflammatory sites
Page 21 and 22: Figure 3: Several sources of PAs ar
Page 23 and 24: chemotherapy and lead to a very lar
Page 25 and 26: Thomas T and Thomas T. Polyamines i
Page 27 and 28: 70 Tülin Aktaç and Elvan Bakar Ma
Page 29 and 30: 72 Tülin Aktaç and Elvan Bakar Ak
Page 31 and 32: 74 Seyhan Altun et al. Altun (1996)
Page 33 and 34: 76 Seyhan Altun et al. increased a
Page 35 and 36: 78 Seyhan Altun et al. PH ratio and
Page 39 and 40: epirubicin + tamoxifen were added t
Page 41 and 42: Murphy B and Muss HB. Hormonal ther
Page 43 and 44: 88 Gülruh Ulako¤lu et al., 1993).
Page 45 and 46: 90 Gülruh Ulako¤lu According to t
Page 49 and 50: pad3 locus from the Col-pad3 mutant
Page 51 and 52: Table 2: Phenotypic interaction bet
Page 53 and 54: locus recognise distinct Peronospor
Page 55 and 56: 102 Narçin Palavan-Ünsal et al. I
Page 57 and 58: 104 Narçin Palavan-Ünsal et al. F
Page 59 and 60: 106 Narçin Palavan-Ünsal et al. F
Page 61 and 62: 108 Narçin Palavan-Ünsal et al. c
Page 63 and 64: 110 Ayfle TABAKO⁄LU-O⁄UZ, Anima
Page 65 and 66: 112 by superscript small letters an
Page 67 and 68: 114 Volume 1, No. 2 Review articles
Page 69:
Journal of Cell and Molecular Biolo
show all

Full Journal - Journal of Cell and Molecular Biology - Haliç Üniversitesi

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?