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T V Hansen

Publications and source records attributed to T V Hansen.

10 recordsLinked to original sources
PubMed2001

Cholecystokinin gene transcription: promoter elements, transcription factors and signaling pathways.

Cholecystokinin (CCK) is a neuropeptide expressed in the small intestine and in the central and peripheral nervous system. CCK gene expression is both spatially and temporally regulated. In neurons CCK production is increased by growth factors, cyclic adenosine 3', 5'-monophosphate (cAMP), dopamine, estrogen, and injury situations, while intestinal CCK expression is mainly regulated by food intake. The function of the proximal CCK promoter has been examined by transfection of human CCK-CAT reporter constructs in cultured cells, DNase I footprinting and gel shift assays. These studies have led to the identification of regulatory elements and transcription factors important for basal and stimulated gene expression and depicted the signaling pathways involved in growth factor and cAMP induced CCK transcription. The review outlines the current knowledge of the regulation of CCK transcription and describes the role of putative transcription factors in tissue-specific CCK gene expression.

Animals↗
PubMed2001

Regulation of neuronal cholecystokinin gene transcription.

Cholecystokinin (CCK) is a neuroendocrine peptide expressed in I-cells of the small intestine and in central and peripheral neurons. Whereas intestinal CCK is involved in the release of pancreatic enzymes and the contraction of the gallbladder, cerebral CCK is implicated in a variety of functions, such as feeding behaviour, anxiety and memory. The expression of CCK is developmentally regulated. Brain CCK mRNA levels are low before birth, but increase markedly shortly after birth and reach adult like patterns of expression three weeks after birth during the final maturation of the central nervous system. In the adult, several substances induce neuronal CCK mRNA expression via activation of transcription factors binding to regulatory elements in the CCK promoter. Recent studies have examined the signaling pathways, transcription factors and regulatory elements involved in cAMP, fibroblast growth factor-2, and calcium-induced CCK gene transcription in neuronal cells. The review describes the signaling pathways and transcription factors involved in neuronal CCK gene transcription.

Animals↗
PubMed2000

Function of the C-36 to T polymorphism in the human cholecystokinin gene promoter.

Cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain, and in man significant quantities are expressed in all regions of the brain.1,2 Therefore, CCK has been implicated in a variety of CNS functions-such as feeding behavior, anxiety, analgesia and memory functions as well as psychiatric disease like panic disorder and schizophrenia (for review, see2,3). Recently, a number of studies have indicated that a C-36 to T transition in the CCK gene promoter Sp1 element4 (Figure 1) is associated with alcoholism and withdrawal symptoms as well as panic disorder.5-7 Moreover, it has been proposed that the polymorphism plays a direct role in the pathogenesis of the disorders by decreasing the expression and synthesis of CCK peptides. The significance of these findings is still unclear and other studies have failed to demonstrate linkage between the polymorphism and alcoholism.8 In this study we examined the function of the C-36 to T transition in transcription of the human CCK gene. We demonstrate that substitution of the C-36 residue causes a slight reduction of Sp1 and Sp3 binding, but this has no effect on transcription in vivo. Moreover, no difference in the response to physiological stimuli was observed. Taken together the results show that the C to T polymorphism does not play a direct role in the pathogenesis of either alcoholism or panic disorder and that a putative association to these disorders is likely to be the result of co-segregation with a linked mutation.

Animals↗
PubMed1999

Negative cooperativity between juxtaposed E-box and cAMP/TPA responsive elements in the cholecystokinin gene promoter.

The promoter of the cholecystokinin (CCK) gene possesses evolutionary conserved juxtaposed E-box and cAMP/TPA responsive elements (CRE/TRE). We have examined the functional interaction of these two sites. As previously noted, c-Jun/c-Fos heterodimers greatly increase promoter activity through association with the CRE/TRE. Mutation of the E-box enhanced the activation by c-Jun/c-Fos, as well as stimulation by forskolin and bFGF, that acts through the CRE/TRE site. Moreover, c-Jun/c-Fos stimulation was inhibited by co-expression of c-Myc and Max. The results indicate that factors associating with the E-box exhibit a negative cooperative effect on the activation via the CRE/TRE element. We propose that this mechanism plays a significant role in CCK gene transcription and other genes with juxtaposed E-box and CRE/TRE.

Animals↗
PubMed1999

Mitogen-activated protein kinase and protein kinase A signaling pathways stimulate cholecystokinin transcription via activation of cyclic adenosine 3',5'-monophosphate response element-binding protein.

Cholecystokinin (CCK) is a potent neuropeptide expressed in the small intestine and in the central nervous system. We have examined the effect of basic fibroblast factor (bFGF) and forskolin on CCK gene transcription and depicted the signaling pathways that lead to promoter activation. bFGF and forskolin stimulated promoter activity via a cAMP response element (CRE)/12-O-tetradecanoylphorbol-13-acetate response element (TRE) located 80 bp upstream from the transcription initiation site. In nuclear extracts from unstimulated as well as stimulated cells, only CRE-binding protein (CREB) and activating transcription factor-1 (ATF-1) bound to the CRE/TRE, and activation was associated with phosphorylation of CREB serine-133 and ATF-1 serine-63. In murine F9 cells, CREB stimulated promoter activity 10-fold in the presence of protein kinase A (PKA), and in SK-N-MC cells activation was inhibited 60-70% by a dominant negative CREB mutant. In contrast, ATF-1 had no effect in F9 cells and exhibited a dominant negative effect in SK-N-MC cells. bFGF stimulation led to phosphorylation of the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal-regulated kinase (ERK) MAPK and promoter activation, phosphorylation of CREB, and GAL4-CREB-dependent transcription were selectively prevented by a dominant negative Ras-mutant, the p38 MAPK-specific inhibitor SB203580, and the MAP/ERK kinase 1 (MEK1) inhibitor PD098059. Forskolin stimulation proceeded via the PKA pathway, and to a minor extent via the p38 and ERK MAPK pathways. We conclude that bFGF and forskolin stimulate the CCK gene promoter via the CRE/TRE(-80) in the proximal promoter region. Signaling proceeds through the p38 MAPK, the ERK MAPK, and the PKA-signaling pathways, which leads to cumulative phosphorylation and activation of CREB. We propose that bFGF in combination with neurotransmitters/neuropeptides coupling to the PKA-signaling pathway play an important role in the control of CCK gene expression.

Activating Transcription Factor 1↗
PubMed1996

Transcriptional regulation of the human cholecystokinin gene: composite action of upstream stimulatory factor, Sp1, and members of the CREB/ATF-AP-1 family of transcription factors.

We have examined cis-elements and trans-acting factors that regulate transcription of the human cholecystokinin (CCK) gene. Transient expression of CCK promoter deletion constructs in human SK-N-MC neuroblastoma cells depicted positive cis-elements between the positions -100 to -92, -84 to -74, and -58 to -37, 5' to the transcription initiation site. Correspondingly, DNase I protection analysis showed that transacting factors bound to elements within these regions. The sequences encompass a putative basic helix-loop-helix leucine zipper (bHLH-ZIP) element, an Sp1 element, and a combined cAMP- and TPA-responsive element (CRE/TRE) at positions -97 to -92, -39 to -34, and -80 to -73, respectively. Mobility and supershift assays demonstrated that upstream stimulatory factor (USF) and Sp1 bind to the former elements and competition experiments confirmed that CREB/ATF and AP-1 bind to the CRE/TRE element. Mutation of the bHLH-ZIP and CRE/TRE elements decreased the activity of the promoter by 65% and 42%, respectively. The activity of the promoter was increased six- and two-fold after stimulation with forskolin and TPA, respectively. Stimulation was eliminated after mutation of the CRE/TRE element. Co-transfection experiments with pRSV-c-jun, pSV-fos, and pRC-RSV-CREB constructs showed that jun, CREB, and AP-1 stimulate transcription. We conclude that USF, Sp1, and members of the CREB/ATF and AP-1 family of transcription factors are the major determinants of CCK gene transcription.

Base Sequence↗
PubMed1994

Homochiral glycerol derivatives by lipase-catalysed racemate resolution.

Various aspects of enzyme-catalysed racemate resolution are discussed by using examples from hydrolysis of butanoates of glycerol derivatives. Primary esters of various 1,2-ketals gave low enantioselectivity (E). The results with secondary esters varied. The highest E value (> 100) was obtained when the primary ether groups were methyl and phenylethyl. For the corresponding methyl, phenyl diether E was observed to increase as the hydrolysis proceeded. The stereochemistry of the products agree with a proposed model for lipases.

Butyrates↗
PubMed1982

The effect of chelating agents on vanadium distribution in the rat body and on uptake by human erythrocytes.

Pentavalent vanadium (V5) as Na48VO3 was given i.p. to male Wistar rats at a dose of 5 mumol/kg in order to study its organ distribution pattern. Two days after injection, kidneys reached a V level of about 28 nmol/g wet weight, followed in decreasing order by spleen, liver, bone, blood plasma, testis, lung, erythrocytes and brain in control rats. A similar distribution pattern was seen after injection of tetravalent vanadium (V4) given as 48VOSO4. Two chelators, desferrioxamine B (Desferal) or Ca-Na3-diethylene triamine pentaacetic acid (DTPA), were given i.p. 24 h after the vanadium injections to different groups of rats at two dosage levels, 30 and 100 mumol/kg. Desferal (30 mumol/kg) reduced the vanadium content of the kidney by 17%, of the liver by 0%, and of the lung by 7%. The corresponding figures for the effect of DTPA (30 mumol/kg) were 7%, plus 15%, and 0%, respectively. At 100 mumol/kg, Desferal reduced the same organ levels by 20%, 26%, and 25%, respectively, and DTPA by 9%, 18%, and 25%, respectively. Both chelators raised faecal excretion at the low level, and both urinary and faecal excretion at the high level. Spleen and bone seemed to bind vanadium to a higher degree than the other organs under examination. Human erythrocytes, when incubated with 48VOSO4 (V4) or Na48VO3 (V5), were found to accumulate nearly the double amount of V5 as compared to V4. Glutathione (GSH) which is the main reducing substance within the erythrocytes, reduced the uptake of V5 to the V4 level when incubated together with GSH before addition to the cell suspension. Pretreating the erythrocytes with diethyl-maleate (DEM) which blocks the reducing SH groups of intracellular GSH, also reduced the uptake of V5. This may indicate a GSH dependent reduction of V5 to V4 within the erythrocytes. Four chelators, among them Desferal and DTPA, were found to reduce the cellbound amount of vanadium, either by extracting vanadium as V4, or by inhibiting uptake by the red blood cells.

Animals↗