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Regulation of nitric oxide synthase II expression by pyrroline-5-carboxylate under hypoxic conditions

  1. Author:
    Donald, S. P.
    Mei, J. M.
    Downing, S. J.
    Phang, J. M.
    1. Year of Conference: 1997
  1. Conference Name: Annual Meeting of the American Association for Cancer Research
    1. 38
    2. Pages: A3733
  2. Type of Work: Meeting Abstract
  1. Abstract:

    The association of a hypoxia-responsive element (HRE) with the nitric oxide synthase II (NOS II) gene indicates that the expression of NOS II may be enhanced during hypoxic events, e.g. in rapidly growing tumors and in the milieu of chronically inflamed tissues. Pyrroline-5-carboxylate (P5C) is a metabolic intermediate of proline, glutamate and ornithine metabolism. It exerts potent redox-regulatory functions and markedly stimulates the flux through the pentose phosphate shunt into 5-phosphoribosyl 1-pyrophosphate and nucleotides. Recent studies in our laboratory demonstrate that P5C induces NOS II expression in a dose-dependent manner at both mRNA and protein levels in J774A.1 mouse macrophages. However, this induction by P5C is demonstrable only under hypoxic conditions (1% O2). Expectedly, hypoxia also shows synergetic effects on NOS II expression induced by endotoxin and cytokines (e.g. lipopolysaccharide and interferon-gamma) at both mRNA and protein levels. Considering that P5C is a carrier of redox potential and an activator of redox-sensitive metabolic pathways, possible interaction of P5C with the HRE of NOS II and its activating factors is an attractive possibility currently under intense investigation.

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