Predominant localization of phospho<i>enol</i>pyruvate carboxykinase mRNA in the periportal zone of rat liver parenchyma demonstrated by in situ hybridization

Bartels, H.; Linnemann, Helga; Jungermann, Kurt

doi:10.1016/0014-5793(89)80459-4

Cited by 53 publications

(33 citation statements)

References 25 publications

(5 reference statements)

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“…The plasmid contained a 1.2-kb rat PCK PstI complementary DNA fragment. 35 Digoxygenin-labeled hybrids were detected according to the manual of Roche-Diagnostics and quantitated by the use of a videodensitometer.…”

Section: Methodsmentioning

confidence: 99%

Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes

2000

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Section: Methodsmentioning

confidence: 99%

Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes

2000

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“…Reporters, expression vectors, and cDNA probes p53CON (Funk et al 1992); CTS1 (Conseiller et al 1998); pcDNA3GR (Sengupta et al 2000b); CMV-LacZ, IGBMC core facility; pBC-IP3.2 (Wasylyk et al 1999); HA-Ub (Treier et al 1994); pBS-␤-actin (IGBMC core facility); pBS-glucose-6-phosphate (Lange et al 1994); pBS-PEPCK (Bartels et al 1989); pRCp53(WT) and pRCp53(22,23) (Lin et al 1994);pxMDM2, px⌬R, pxC462A (Argentini et al 2000); pEGGFP-C1 (Clonetech). (Bunz et al 1998).…”

Section: Recombinantsmentioning

confidence: 99%

Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2

Sengupta¹,

Wasylyk²

2001

Genes Dev.

109

102

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The glucocorticoid receptor (GR) and the tumor supressor p53 mediate different stress responses. We have studied the mechanism of their mutual inhibition in normal endothelial cells (HUVEC) in response to hypoxia, a physiological stress, and mitomycin C, which damages DNA. Dexamethasone (Dex) stimulates the degradation of endogenous GR and p53 by the proteasome pathway in HUVEC under hypoxia and mitomycin C treatments, and also in hepatoma cells (HepG2) under normoxia. Dex inhibits the functions of p53 (apoptosis, Bax, and p21 WAF1/CIP1 expression) and GR (PEPCK and G-6-Pase expression). Endogenous p53 and GR form a ligand-dependent trimeric complex with Hdm2 in the cytoplasm. Disruption of the p53-HDM2 interaction prevents Dex-induced ubiquitylation of GR and p53. The ubiquitylation of GR requires p53, the interaction of p53 with Hdm2, and E3 ligase activity of Hdm2. These results provide a mechanistic basis for GR and p53 acting as opposing forces in the decision between cell death and survival. The development of most tumors is associated with loss of function of the tumor suppressor p53. Different physiological stress, including DNA damage and hypoxia, activate p53. p53 is a transcription factor that regulates genes involved in growth arrest and apoptosis. p53 is down-regulated by its target gene product Mdm2 (human homolog Hdm2). Mdm2 forms an autoregulatory loop with p53 by binding to its N-terminal domain, inhibiting its transcriptional activity and increasing its degradation by the ubiquitin proteasome pathway (for reviews, see Jimenez et al. 1999;Lakin and Jackson 1999;Sionov and Haupt 1999). Mdm2 is a RING finger-dependent ubiquitin protein ligase for p53 and itself (Argentini et al. 2000;Fang et al. 2000;Honda and Yasuda 2000). Mdm2 also inhibits p53 by nuclear export through a mechanism involving either the nuclear export signal (NES) of Mdm2 (Tao and Levine 1999) or the RING finger of Mdm2 and the NES of p53 (Boyd et al. 2000;Geyer et al. 2000). The NES of p53 is masked in the transcriptionally active heterodimer, but is exposed in the monomeric form of p53 ). MdmX, a Mdm2 homolog that lacks a NES, stabilizes p53 by retention in the nucleus (Jackson and Berberich 2000;Stad et al. 2000). Nuclear p53 levels can also be maintained by ARF, which blocks nucleo-cytoplasmic shuttling of Mdm2 (Sherr and Weber 2000). Most studies of p53 involve DNA damaging drugs and radiation. Much less is known about the physiological stress, hypoxia. Under hypoxic conditions, p53 is stabilized by mitochondria through a redox-dependent mechanism (Chandel et al. 2000) and by HIF-1␣ , whereas p53 induces degradation of HIF-1␣ (Ravi et al. 2000). The response to hypoxia in vivo also involves the glucocorticoid receptor (GR) (Bauer et al. 1999).GR is a member of the steroid receptor superfamily that mediates physiological processes controlled by glucocorticoids. In the unbound state GR is located in the cytoplasm bound to chaperones. Upon ligand binding the chaperones dissociate, exposing the NLS that enables GR to enter the n...

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“…Carbamoylphosphate synthase (I) protein [6] and mRNA [7] have been shown to be localized in a large periportal domain that is contiguous with the small glutamine synthetase-expressing pericentral domain. Phosphoenolpyruvate carboxykinase protein [8] and mRNA [9,10] are also present in a periportal area which is, however, not as large as that of the urea cycle enzymes. There is functional evidence that glutaminase is predominantly present in the periportal hepatocytes [ 111, and it has been shown that isolated periportal hepatocytes have a 2-3 fold higher glutaminase activity and mRNA level than pericentral hepatocytes [ 121.…”

Section: Introductionmentioning

confidence: 99%

Hepatic glutaminase mRNA is confined to part of the urea cycle domain in the adult rodent liver lobule

et al. 1994

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Ah&actThis in situ hybridization study describes the developmental appearance of the lobular distribution of the mRNA encoding hepatic glutaminase in normal rat liver. Glutaminase has been proposed to provide the urea cycle with ammonia [Hiiussinger and Gerok (1983) Eur. J. Biochem. 133,26%275]. Hence, the (developmental) pattern of expression of the mRNA would be expected to be closely linked to that of the urea cycle enzymes. From embryonic day 20 onward, hepatic glutaminase mRNA can be detected along the entire porto-central axis, with predominant expression in the portal area. In the adult phenotype, which is acquired at the end of the first postnatal week, glutarninase mRNA is no longer present along the entire porto-central distance but has become confined to a relatively small periportal domain in which the expression decreases in a porto-central direction. Thus, in contrast to the large periportal domain, in which the urea cycle enzymes are expressed, the glutaminase mRNAexpressing domain is much smaller and not contiguous with the glutamine synthase mRNA-expressing pericentral domain, leaving a midlobular area that is devoid of glutaminase mRNA. A similar pattern of distribution was found in adult mouse liver. The significance of these observations is that, within the liver lobules, there is an area in which glutaminase is not expressed and, hence, glutamine can not be the substrate for urea synthesis.

show abstract

Predominant localization of phosphoenolpyruvate carboxykinase mRNA in the periportal zone of rat liver parenchyma demonstrated by in situ hybridization

Cited by 53 publications

References 25 publications

Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes

Phosphatidylinositol 3-kinase and protein kinase C contribute to the inhibition by interleukin 6 of phosphoenolpyruvate carboxykinase gene expression in cultured rat hepatocytes

Ligand-dependent interaction of the glucocorticoid receptor with p53 enhances their degradation by Hdm2

Hepatic glutaminase mRNA is confined to part of the urea cycle domain in the adult rodent liver lobule

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