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Titolo:
Cell density mediated pericellular hypoxia leads to induction of HIF-1 alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways
Autore:
Sheta, EA; Trout, H; Gildea, JJ; Harding, MA; Theodorescu, D;
Indirizzi:
Univ Virginia, Hlth Sci Ctr, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA Univ Virginia Charlottesville VA USA 22908 Charlottesville, VA 22908 USA
Titolo Testata:
ONCOGENE
fascicolo: 52, volume: 20, anno: 2001,
pagine: 7624 - 7634
SICI:
0950-9232(20011115)20:52<7624:CDMPHL>2.0.ZU;2-H
Fonte:
ISI
Lingua:
ENG
Soggetto:
ENDOTHELIAL GROWTH-FACTOR; INDUCIBLE FACTOR-I; PROTEIN-TYROSINE PHOSPHORYLATION; HUMAN ERYTHROPOIETIN GENE; COLON-CARCINOMA CELLS; HUMAN PROSTATE-CANCER; SMOOTH-MUSCLE CELLS; FACTOR EXPRESSION; DEPENDENT REGULATION; TUMOR ANGIOGENESIS;
Keywords:
cell hypoxia; oxygen; nuclear proteins; nitric oxide; Ras proteins;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
62
Recensione:
Indirizzi per estratti:
Indirizzo: Theodorescu, D Univ Virginia, Hlth Sci Ctr, Dept Mol Physiol & Biol Phys, Box 422, Charlottesville, VA 22908 USA Univ Virginia Box 422 Charlottesville VA USA 22908 2908 USA
Citazione:
E.A. Sheta et al., "Cell density mediated pericellular hypoxia leads to induction of HIF-1 alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways", ONCOGENE, 20(52), 2001, pp. 7624-7634

Abstract

Environmental signals in the cellular milieu such as hypoxia, growth factors, extracellular matrix (ECM), or cell-surface molecules on adjacent cellscan activate signaling pathways that communicate the state of the environment to the nucleus. Several groups have evaluated gene expression or signaling pathways in response to increasing cell density as an in vitro surrogate for in vivo cell-cell interactions. These studies have also perhaps assumed that cells grown at various densities in standard in vitro incubator conditions do not have different pericellular oxygen levels. However, pericellular hypoxia can be induced by increasing cell density, which can exert profound influences on the target cell lines and may explain a number of findings previously attributed to normoxic cell-cell interactions. Thus, we first sought to test the hypothesis that cell-cell interactions as evaluated bythe surrogate approach of increasing in vitro cell density in routine normoxic culture conditions results in pericellular hypoxia in prostate cancer cells. Second, we sought to evaluate whether such interactions affect transcription mediated by the hypoxia response element (HRE). Thirdly, we soughtto elucidate the signal transduction pathways mediating the induction of HRE in response to cell density induced pericellular hypoxia in routine normoxic culture conditions. Our results indicate that paracrine cell interactions can induce nuclear localization of HIF-1a protein and this translocation is associated with strong stimulation of the HRE-reporter activity. We also make the novel observation that cell density-induced activity of the HREis dependent on nitric oxide production, which acts as a diffusible paracrine factor secreted by densely cultured cells. These results suggest that paracrine cell interactions associated with pericellular hypoxia lead to thephysiological induction of HRE activity via the cooperative action of Ras,MEK1, HIF-1a via pericellular diffusion of nitric oxide. In addition, these results highlight the importance of examining pericellular hypoxia as a possible stimulus in experiments involving in vitro cell density manipulation even in routine normoxic culture conditions.

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Documento generato il 19/09/20 alle ore 17:01:19