Regulation of mRNA levels for five urea cycle enzymes in rat liver by diet, cyclic AMP, and glucocorticoids

Morris, Sidney M.; Moncman, Carole L.; Rand, Katherine D.; Dizikes, George J.; Cederbaum, Stephen D.; O’Brien, William E.

doi:10.1016/0003-9861(87)90455-3

Cited by 124 publications

(74 citation statements)

References 60 publications

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“…Earlier studies on the promoter region of liver arginase had revealed sequences matching CRE and glucocorticoid-responsive element (28), and the expression of liver arginase was up-regulated by cAMP and glucocorticoid (29,30). In contrast to the liver cells, we found that macrophage arginase is up-regulated by a cAMP analogue but not by dexamethasone (Fig.…”

Section: Discussionmentioning

confidence: 45%

The Involvement of Tyrosine Kinases, Cyclic AMP/Protein Kinase A, and p38 Mitogen-Activated Protein Kinase in IL-13-Mediated Arginase I Induction in Macrophages: Its Implications in IL-13-Inhibited Nitric Oxide Production

Chang

Zoghi

Liao

et al. 2000

The Journal of Immunology

105

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In macrophages, l-arginine can be used by NO synthase and arginase to form NO and urea, respectively. Therefore, activation of arginase may be an effective mechanism for regulating NO production in macrophages through substrate competition. Here, we examined whether IL-13 up-regulates arginase and thus reduces NO production from LPS-activated macrophages. The signaling molecules involved in IL-13-induced arginase activation were also determined. Results showed that IL-13 increased arginase activity through de novo synthesis of the arginase I mRNA and protein. The activation of arginase was preceded by a transient increase in intracellular cAMP, tyrosine kinase phosphorylation, and p38 mitogen-activated protein kinase (MAPK) activation. Exogenous cAMP also increased arginase activity and enhanced the effect of IL-13 on arginase induction. The induction of arginase was abolished by a protein kinase A (PKA) inhibitor, KT5720, and was down-regulated by tyrosine kinase inhibitors and a p38 MAPK inhibitor, SB203580. However, inhibition of p38 MAPK had no effect on either the IL-13-increased intracellular cAMP or the exogenous cAMP-induced arginase activation, suggesting that p38 MAPK signaling is parallel to the cAMP/PKA pathway. Furthermore, the induction of arginase was insensitive to the protein kinase C and p44/p42 MAPK kinase inhibitors. Finally, IL-13 significantly inhibited NO production from LPS-activated macrophages, and this effect was reversed by an arginase inhibitor, l-norvaline. Together, these data demonstrate for the first time that IL-13 down-regulates NO production through arginase induction via cAMP/PKA, tyrosine kinase, and p38 MAPK signalings and underline the importance of arginase in the immunosuppressive activity of IL-13 in activated macrophages.

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Section: Discussionmentioning

confidence: 45%

The Involvement of Tyrosine Kinases, Cyclic AMP/Protein Kinase A, and p38 Mitogen-Activated Protein Kinase in IL-13-Mediated Arginase I Induction in Macrophages: Its Implications in IL-13-Inhibited Nitric Oxide Production

Chang

Zoghi

Liao

et al. 2000

The Journal of Immunology

105

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“…Multiple factors have been shown to positively and negatively influence ASS gene and may be tissue specific. Several investigators have demonstrated that glucocorticoid, glucagon and cyclin AMP increase ASS expression whereas fatty acids repress ASS expression [58][59][60][61][62][63][64][65]. Insulin and growth hormone have negative influence on ASS in liver tissue but no effect in other tissue [66][67][68].…”

Section: Why Ass Is Not Expressed In Certain Tumor Types ?mentioning

confidence: 99%

Arginine Deprivation as a Targeted Therapy for Cancer

Feun

You

et al. 2008

CPD

196

188

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Certain cancers may be auxotrophic for a particular amino acid and amino acid deprivation is one method to treat these tumors. Arginine deprivation is a novel approach to target tumors which lack argininosuccinate synthetase (ASS) expression. ASS is a key enzyme which converts citrulline to arginine. Tumors which usually do not express ASS include melanoma, hepatocellular carcinoma, some mesotheliomas and some renal cell cancers. Arginine can be degraded by several enzymes including arginine deiminase (ADI). Although ADI is a microbial enzyme from mycoplasma, it has high affinity to arginine and catalyzes arginine to citrulline and ammonia. Citrulline can be recycled back to arginine in normal cells which express ASS, whereas ASS(−) tumor cells cannot. A pegylated form of ADI (ADI-PEG20) has been formulated and has shown in vitro and in vivo activity against melanoma and hepatocellular carcinoma. ADI-PEG20 induces apoptosis in melanoma cell lines. However, arginine deprivation can also induce ASS expression in certain melanoma cell lines which can lead to in-vitro drug resistance. Phase I and II clinical trials with ADI-PEG20 have been conducted in patients with melanoma and hepatocellular carcinoma and antitumor activity has been demonstrated in both cancers. This article reviews our laboratory and clinical experience as well as others with ADI-PEG20 as an antineoplastic agent. Future direction in utilizing this agent is also discussed.

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“…The steady-state degradation rates found in these experiments fall within the range of 0Á09± 0Á3ah, which is slower than the rates of the highly inducible enzymes such as tyrosine aminotransferase (EC 2.6.1.5) or tryptophan pyrrolase, but in line with many other liver enzymes (Waterlow et al 1978). The concentrations of the mRNA for these enzymes were found to increase with increases in their amounts and activity (Mori et al 1981;Morris et al 1987), which suggests regulation of gene expression and transcription (Jackson et al 1986), but later work indicated that the situation is more complicated, with different control mechanisms for the different enzymes (Ulbright & Snodgrass, 1993). How the activities of the two mitochondrial and three cytoplasmic enzymes are coordinated is, as far as I know, unknown.…”

Section: The Biochemical Evidencementioning

confidence: 99%

The mysteries of nitrogen balance

Waterlow¹

1999

Nutr. Res. Rev.

113

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The ®rst part of this review is concerned with the balance between N input and output as urinary urea. I start with some observations on classical biochemical studies of the operation of the urea cycle. According to Krebs, the cycle is instantaneous and automatic, as a result of the irreversibility of the ®rst enzyme, carbamoyl-phosphate synthetase 1 (EC 6.3.5.5; CPS-I), and it should be able to handle many times the normal input to the cycle. It is now generally agreed that acetyl glutamate is a necessary co-factor for CPS-1, but not a regulator. There is abundant evidence that changes in dietary protein supply induce coordinated changes in the amounts of all ®ve urea-cycle enzymes. How this coordination is achieved, and why it should be necessary in view of the properties of the cycle mentioned above, is unknown. At the physiological level it is not clear how a change in protein intake is translated into a change of urea cycle activity. It is very unlikely that the signal is an alteration in the plasma concentration either of total amino-N or of any single amino acid. The immediate substrates of the urea cycle are NH 3 and aspartate, but there have been no measurements of their concentration in the liver in relation to urea production. Measurements of urea kinetics have shown that in many cases urea production exceeds N intake, and it is only through transfer of some of the urea produced to the colon, where it is hydrolysed to NH 3 , that it is possible to achieve N balance. It is beginning to look as if this process is regulated, possibly through the operation of recently discovered urea transporters in the kidney and colon. The second part of the review deals with the synthesis and breakdown of protein. The evidence on whole-body protein turnover under a variety of conditions strongly suggests that the components of turnover, including amino acid oxidation, are in¯uenced and perhaps regulated by amino acid supply or amino acid concentration, with insulin playing an important but secondary role. Molecular biology has provided a great deal of information about the complex processes of protein synthesis and breakdown, but so far has nothing to say about how they are coordinated so that in the steady state they are equal. A simple hypothesis is proposed to ®ll this gap, based on the self-evident fact that for two processes to be coordinated they must have some factor in common. This common factor is the amino acid pool, which provides the substrates for synthesis and represents the products of breakdown. The review concludes that although the achievement and maintenance of N balance is a fact of life that we tend to take for granted, there are many features of it that are not understood, principally the control of urea production and excretion to match the intake, and the coordination of protein synthesis and breakdown to maintain a relatively constant lean body mass.

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Regulation of mRNA levels for five urea cycle enzymes in rat liver by diet, cyclic AMP, and glucocorticoids

Cited by 124 publications

References 60 publications

The Involvement of Tyrosine Kinases, Cyclic AMP/Protein Kinase A, and p38 Mitogen-Activated Protein Kinase in IL-13-Mediated Arginase I Induction in Macrophages: Its Implications in IL-13-Inhibited Nitric Oxide Production

The Involvement of Tyrosine Kinases, Cyclic AMP/Protein Kinase A, and p38 Mitogen-Activated Protein Kinase in IL-13-Mediated Arginase I Induction in Macrophages: Its Implications in IL-13-Inhibited Nitric Oxide Production

Arginine Deprivation as a Targeted Therapy for Cancer

The mysteries of nitrogen balance

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