|
|
| [an error occurred while processing this directive] |
Mathematical model of erythrocyte maturation regulationHematopoietic tissue belongs to the self-renewing systems of the organism that are operated through specific regulatory and self-regulatory mechanisms. Maintenance of certain amount of erythroid cells is one of the necessary conditions for the organism to perform its vital functions. From this standpoint, theoretical research into proliferation and differentiation of hematopoietic tissue cells is of both basic and applied biomedical importance. The main stages of erythrocyte maturation are regulated by the gene network described in GeneNet database. The hormone erythropoietin interacts with immature erythroid cells (erythroid stem progenitors of CFU-E type) and stimulates their proliferation, syntheses of hemoglobin, and the enzymes involved in heme biosynthesis, that is, maturation and differentiation of erythroid progenitors. Low partial pressure of oxygen in venous blood (hypoxia) is another stimulator of erythropoietin synthesis. Interacting with cell receptor, erythropoietin activates the transcription factor GATA-1, a key regulator of erythrocyte differentiation. GATA-1 stimulates syntheses of a -, b -globins, and the enzymes of heme biosynthesis. In addition, GATA-1 activates its own gene and gene of erythropoietin receptor (positive feedback). Heme, a -globin, and b -globin form hemoglobin, the major component of the mature erythrocyte. This biosystem functions according to completely different pattern compared to the system described in the previous section. This gene network is inactive until erythropoietin triggers it to start the irreversible process of erythrocyte maturation, where positive feedbacks are predominant. The model of this gene network performance is described as a sequence of events occurring in the maturating cells of the erythroid lineage. The erythropoietin-responsive progenitor cell opens the lineage closed by mature erythrocyte. The model comprises 119 elementary processes, 68 products, and 178 constants. Brief descriptions of the gene network objects presented in the model as dynamic variables given in the table. Table. The objects of gene network of erythrocyte maturation regulation presented in the models as dynamic variable
Direct experimental data [Dailey and Karr, 1987; Volland and Felix, 1984; Felix and Brouillet, 1990; Frydman and Feinstein, 1984; Gibbs et al., 1985; Kohno et al., 1996; Mazzetti and Tomio, 1988; Mukerji and Pimstone, 1987; Nakahashi et al., 1990; Smythe and Williams, 1988; Scholnick et al., 1972; Siepker et al., 1987; Tan et al., 1996; Taketani and Tokunaga, 1981; Yoshinaga and Sano, 1980] were used to specify a number of constants. The rest parameters were determined through numerical experiments [Ratushny et al., 2000b] using quantitative and qualitative characteristics known from the literature [Kuhn, 1994; Ponka, 1997]. The model developed predicts that productions of several components of the system follow oscillatory dynamics (Fig. 6). The reason for this pattern is interaction of positive and negative feedbacks with domination of the former regulation mode. BibliographyDailey H. A., Karr S. W. Purification and
characterization of murine protoporphyrinogen oxidase. Biochemistry, 1987, 26,
2697-2701. Volland C., Felix F. Isolation and properties of
5-aminolevulinate synthase from the yeast Saccharomyces cerevisiae. European Journal
of Biochemistry, 1984, 142(3), 551-557. Felix F., Brouillet N. Purification and properties
of uroporphyrinogen decarboxylase from Saccharomyces cerevisiae. Yeast uroporphyrinogen
decarboxylase. European Journal of Biochemistry, 1990, 188(2), 393-403. Frydman R. B., Feinstein G. Studies on
porphobilinogen deaminase and uroporphyrinogen III cosynthase from human erythrocytes. Biochimica
et Biophysica Acta, 1974, 350(2), 358-373. Gibbs P. N. B., Chaudhry A.-G., Jordan P. M.
Purification and properties of 5-aminolevulinate hydratase from human erythrocytes. The
Biochemical Journal, 1985, 230(1), 25-34. Kohno H., Furukawa T., Tokunaga R., Taketani S.,
Yoshinaga T. Mouse coproporphyrinogen oxidase is a copper-containing enzyme: expression in
Escherichia coli and site-directed mutagenesis. Biochimica et Biophysica Acta, 1996,
1292(1), 156-162. Mazzetti M. B., Tomio J. M. Characterization of
porphobilinogen deaminase from rat liver. Biochimica et Biophysica Acta, 1988, 957(1),
97-104. Mukerji S. K., Pimstone N. R. Evidence for two
uroporphyrinogen decarboxylase isoenzymes in human erythrocytes. Biochemical and
Biophysical Research Communications, 1987, 146(3), 1196-1203. Nakahashi Y., Taketani S., Sameshima Y.,
Tokunaga R. Characterization of ferrochelatase in kidney and erythroleukemia cells. Biochimica
et Biophysica Acta, 1990, 1037(3), 321-327. Smythe E., Williams D. C. A Simple rapid
purification scheme for hydroxymethylbilane synthase from human erythrocytes. The
Biochemical Journal, 1988, 251(1), 237-241. Scholnick P. L., Hammaker L. E., Marver H. S.
Soluble 5-aminolevulinic acid synthetase of rat liver. I. Some properties of the partially
purified enzyme. The Journal of Biological Chemistry, 1972, 247(13), 4126-4131. Siepker L.J., Ford M., de Kock R., Kramer S.
Purification of bovine protoporphyrinogen oxidase: immunological cross-reactivity and
structural relationship to ferrochelatase. Biochimica et Biophysica Acta, 1987,
913(3), 349-358. Tan D., Ferreira G. C. Active site of
5-aminolevulinate synthase resides at the subunit interface. Evidence from in vivo
heterodimer formation. Biochemistry, 1996, 35(27), 8934-8941, 1996. Taketani S., Tokunaga R. Rat liver
ferrochelatase. Purification, properties and stimulation by fatty acid. Purification,
properties and stimulation by fatty acid. Journal of Biological Chemistry, 1981,
256(24), 12748-12753. Yoshinaga T., Sano S. Coproporphyrinogen
oxidase. I. Purification, properties, and activation by phospholipids. Journal of
Biological Chemistry, 1980, 255(10), 4722-4726. Ratushny A.V.,
Podkolodnaya O.A., Ananko E.A., Likhoshvai V.A. Mathematical model of erythroid cell
differentiation regulation. Proceeding of the second international conference on
bioinformatics or genome regulation and structure, Novosibirsk, 2000b, V.1, 203-206. Kuhn L.C. Molecular regulation of iron proteins. Bailliere’s
Clinical Haemotology-V.7, No. 4, December 1994. Ponka P. Tissue-specific regulation of iron
metabolism and heme synthesis: distinct control mechanism in erythroid cells. Blood,
V. 89, No 1, January 1, 1997. |
