Acute hypoxia increases ornithine decarboxylase activity and polyamine concentrations in fetal rat brain.

Longo, Lawrence D.; Packianathan, Satyaseelan; McQueary, Jeffrey A.; Stagg, Robert B.; Byus, Craig V.; Cain, Christopher D.

doi:10.1073/pnas.90.2.692

Cited by 37 publications

(19 citation statements)

References 37 publications

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“…It was previously reported that hypoxic exposure of pregnant rats caused a transient induction of ODC activity in the brain of the fetus (48). In contrast with our data, hypoxia was shown to upregulate the level of ODC mRNA.…”

Section: Discussioncontrasting

confidence: 56%

Hypoxia-Mediated Induction of the Polyamine System Provides Opportunities for Tumor Growth Inhibition by Combined Targeting of Vascular Endothelial Growth Factor and Ornithine Decarboxylase

Svensson¹,

Welch²,

Kucharzewska³

et al. 2008

Cancer Research

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Hypoxia is a hallmark of solid tumors, which may offer opportunities for targeted therapies of cancer; however, the mechanisms that link hypoxia to malignant transformation and tumor progression are not fully understood. Here, we show that up-regulation of the polyamine system promotes cancer cell survival during hypoxic stress. Hypoxia was found to induce polyamine transport and the key enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), in a variety of cancer cell lines. Increased ODC protein expression was shown in hypoxic, GLUT-1-expressing regions of tumor spheroids and experimental tumors, as well as in clinical tumor specimens. Hypoxic induction of the polyamine system was dependent on antizyme inhibitor (i.e., a key positive regulator of ODC and polyamine transport), as shown by RNA interference experiments. Interestingly, depletion of the polyamines during hypoxia resulted in increased apoptosis, which indicates an essential role of the polyamines in cancer cell adaptation to hypoxic stress. These results were supported by experiments in an in vivo glioma tumor model, showing significantly enhanced antitumor effects of the antiangiogenic, humanized anti-vascular endothelial growth factor (VEGF) antibody bevacizumab when used in combination with the well-established, irreversible inhibitor of ODC, A-difluoromethylornithine. Our results provide important insights into the hypoxic stress response in malignant cells and implicate combined targeting of VEGF and ODC as an alternative strategy to treat cancer disease. [Cancer Res 2008;68(22):9291-301]

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Section: Discussioncontrasting

confidence: 56%

Hypoxia-Mediated Induction of the Polyamine System Provides Opportunities for Tumor Growth Inhibition by Combined Targeting of Vascular Endothelial Growth Factor and Ornithine Decarboxylase

Svensson¹,

Welch²,

Kucharzewska³

et al. 2008

Cancer Research

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“…Although there is no information related to the effect of hypoxia on CK2, hypoxia is known to increase the levels of polyamines in the lung (34), which in turn are strong activators of CK2 (35,36). Our finding that the CK2 inhibitor partially blocks hypoxia-stimulated XDH/XO phosphorylation and hypoxia-stimulated XDH/XO activity strongly suggests a role for this kinase in mediating the effects of hypoxia on XDH/XO.…”

Section: Table I Percent Of Inhibition Of Xdh/xo Phospholabelingmentioning

confidence: 46%

Phosphorylation of Xanthine Dehydrogenase/Oxidase in Hypoxia

Kayyali

Donaldson

Huang

et al. 2001

Journal of Biological Chemistry

109

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The enzyme xanthine oxidase (XO) has been implicated in the pathogenesis of several disease processes, such as ischemia-reperfusion injury, because of its ability to generate reactive oxygen species. The expression of XO and its precursor xanthine dehydrogenase (XDH) is regulated at pre-and posttranslational levels by agents such as lipopolysaccharide and hypoxia. Posttranslational modification of the protein, for example through thiol oxidation or proteolysis, has been shown to be important in converting XDH to XO. The possibility of posttranslational modification of XDH/XO through phosphorylation has not been adequately investigated in mammalian cells, and studies have reported conflicting results. The present report demonstrates that XDH/XO is phosphorylated in rat pulmonary microvascular endothelial cells (RPMEC) and that phosphorylation is greatly increased (ϳ50-fold) in response to acute hypoxia (4 h). XDH/XO phosphorylation appears to be mediated, at least in part, by casein kinase II and p38 kinase as inhibitors of these kinases partially prevent XDH/XO phosphorylation. In addition, the results indicate that p38 kinase, a stress-activated kinase, becomes activated in response to hypoxia (an ϳ4-fold increase after 1 h of exposure of RPMEC to hypoxia) further supporting a role for this kinase in hypoxia-stimulated XDH/XO phosphorylation. Finally, hypoxia-induced XDH/XO phosphorylation is accompanied by a 2-fold increase in XDH/XO activity, which is prevented by inhibitors of phosphorylation. In summary, this study shows that XDH/XO is phosphorylated in hypoxic RPMEC through a mechanism involving p38 kinase and casein kinase II and that phosphorylation is necessary for hypoxia-induced enzymatic activation.Xanthine dehydrogenase is the rate-limiting step in the catabolism of purines, where it catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid. In this reaction, XDH 1 utilizes NAD ϩ preferentially as the electron acceptor. However, when XDH is converted to XO, the preferred electron acceptor becomes molecular oxygen resulting in the formation of superoxide and hydrogen peroxide. This generation of reactive oxygen species is thought to be the basis of XDH/XO involvement in various pathological conditions such as ischemia-reperfusion injury. Reversible conversion of XDH to XO can occur after the oxidation of eight cysteine residues in the molecule into four cystines by agents such as pyrimidines or oxidized glutathione (1, 2). This conversion may be reversed upon the addition of reducing agents such as dithiothreitol. XDH can also be converted into XO irreversibly through proteolysis (3). Experimental proteolysis by trypsin has allowed the identification of three different parts of the molecule: a 20-kDa N-terminal fragment, a 40-kDa flavin-binding fragment, and an 80-kDa molybdopterin-binding fragment, all of which remain attached after proteolysis (3). It is believed that both reversible and irreversible conversion of XDH to XO are due to conformational changes in the molecule that...

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“…Another area of focus of hypoxia studies at LLU in the 1990s was on the role of parenchymal ornithine decarboxylase as a sensor and/or mediator of the cerebral effects of hypoxia [67]. These unique studies revealed that acute hypoxia increases ornithine decarboxylase activity and polyamine concentrations in fetal brain [67] through pathways that can also be activated by-administration of CO to the mother [68].…”

Section: The 1990s: Growing Interest In Fetal Cerebral Vascular Biomentioning

confidence: 99%

“…These unique studies revealed that acute hypoxia increases ornithine decarboxylase activity and polyamine concentrations in fetal brain [67] through pathways that can also be activated by-administration of CO to the mother [68]. Interestingly, these effects of hypoxia could be elicited even in newborn brain slice preparations [69], and appeared to be mediated by oxygen radicals [70], indicating the fundamental cellular nature of the effects of cerebral hypoxia.…”

Section: The 1990s: Growing Interest In Fetal Cerebral Vascular Biomentioning

confidence: 99%

The Fetal Cerebral Circulation: Three Decades of Exploration by the LLU Center for Perinatal Biology

Pearce

2014

Advances in Fetal and Neonatal Physiology

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For more than three decades, research programs in the Center of Perinatal Biology have focused on the vascular biology of the fetal cerebral circulation. In the 1980s, research in the Center demonstrated that cerebral auto-regulation operated over a narrower pressure range, and was more vulnerable to insults, in fetuses than in adults. Other studies were among the first to establish that compared to adult cerebral arteries, fetal cerebral arteries were more hydrated, contained smaller smooth muscle cells and less connective tissue, and had endothelium less capable of producing NO. Work in the 1990s revealed that pregnancy depressed reactivity to NO in extra-cerebral arteries, but elevated it in cerebral arteries through effects involving changes in cGMP metabolism. Comparative studies verified that fetal lamb cerebral arteries were an excellent model for cerebral arteries from human infants. Biochemical studies demonstrated that cGMP metabolism was dramatically upregulated, but that contraction was far more dependent on calcium influx, in fetal compared to adult cerebral arteries. Further studies established that chronic hypoxia accelerates functional maturation of fetal cerebral arteries, as indicated by increased contractile responses to adrenergic agonists and perivascular adrenergic nerves. In the 2000s, studies of signal transduction established age-dependent roles for PKG, PKC, PKA, ERK, ODC, IP3, myofilament calcium sensitivity, and many other mechanisms. These diverse studies clearly demonstrated that fetal cerebral arteries were functionally quite distinct compared to adult cerebral arteries. In the current decade, research in the Center has expanded to a more molecular focus on epigenetic mechanisms and their role in fetal vascular adaptation to chronic hypoxia, maternal drug abuse, and nutrient deprivation. Overall, the past three decades have transformed thinking about, and understanding of, the fetal cerebral circulation due in no small part to the sustained research efforts by faculty and staff in the Center for Perinatal Biology.

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Acute hypoxia increases ornithine decarboxylase activity and polyamine concentrations in fetal rat brain.

Cited by 37 publications

References 37 publications

Hypoxia-Mediated Induction of the Polyamine System Provides Opportunities for Tumor Growth Inhibition by Combined Targeting of Vascular Endothelial Growth Factor and Ornithine Decarboxylase

Hypoxia-Mediated Induction of the Polyamine System Provides Opportunities for Tumor Growth Inhibition by Combined Targeting of Vascular Endothelial Growth Factor and Ornithine Decarboxylase

Phosphorylation of Xanthine Dehydrogenase/Oxidase in Hypoxia

The Fetal Cerebral Circulation: Three Decades of Exploration by the LLU Center for Perinatal Biology

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