Abstract:
:The mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in intracellular signaling, and this cascade may impinge on cAMP response elements (CREs) of target genes. Both the MAPK pathway and chromogranin A expression may be activated by cytosolic calcium influx, and calcium-dependent signals map onto the chromogranin A promoter proximal CRE. We therefore probed the role of the MAPK pathway in chromogranin A biosynthesis after secretory stimulation of PC12 pheochromocytoma cells by the nicotinic cholinergic pathway, the physiological secretory trigger. Chemical inhibition of either MAPK or MAPK kinase blocked the response of a transfected chromogranin A promoter to nicotine or protein kinase C activation [by phorbol-12-myristate-13-acetate (PMA)], although nicotine-evoked catecholamine secretion was unaffected. Activation of the MAP kinase cascade (Ras, Raf, MAPK, or CREB kinase) by cotransfection of pathway components stimulated the chromogranin A promoter. Cotransfection of MAPK pathway dominant negative mutants (for Raf, MAPK, or CREB kinase) blocked nicotinic or PMA activation of chromogranin A, although a dominant negative Ras mutant was without effect. MAPK pathway enzymatic activity was stimulated by both nicotine and PMA. Point mutations of the chromogranin A CRE suggested that this element was necessary in cis for stimulation by nicotine, PMA, or chemical activation of the MAPK pathway. Transfer of the CRE to a heterologous promoter conferred inducibility by not only nicotine or cAMP but also MAPK activation. Expression of the CREB antagonist KCREB blocked the response of the chromogranin A promoter to nicotine, cAMP, or MAPK pathway activation by either chemical stimulation or cotransfection of active cascade components. Chromogranin A mRNA responded to MAPK pathway manipulation in a fashion similar to the transfected chromogranin A promoter, in both direction and magnitude. We conclude that the MAPK pathway is a necessary intermediate in signaling from the nicotinic receptor to secretory protein transcription, although not to catecholamine secretion. In trans, this response seems to involve the following signal cascade: protein kinase C --> Raf --> MAPK kinase --> MAPK --> CREB kinase --> CREB. In cis, activation by the cascade maps onto the chromogranin A promoter proximal CRE, which is both necessary and sufficient to confer the response.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Tang K,Wu H,Mahata SK,O'Connor DTdoi
10.1124/mol.54.1.59subject
Has Abstractpub_date
1998-07-01 00:00:00pages
59-69issue
1eissn
0026-895Xissn
1521-0111journal_volume
54pub_type
杂志文章abstract::Pregnanolone [5 beta-pregnan-3 alpha-ol-20-one (5 beta 3 alpha)] and allopregnanolone [5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha)] are neuroactive steroids that are reduced metabolites of progesterone. Both 5 beta 3 alpha and 5 alpha 3 alpha are potent positive modulators of the gamma-aminobutyric acid respon...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-07-01 00:00:00
abstract::PC-12 cells, derived from a rat pheochromocytoma, were found to take up tritiated serotonin ([3H]5-HT) from the external medium by means of a saturable mechanism which follows Michaelis-Menten kinetics. The apparent Km of uptake was 0.39 microM and the Vmax was 0.40 pmole/min/10(6) cells. The uptake was temperature-de...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-03-01 00:00:00
abstract::delta-Opioid receptor (DOR) promoter exhibited a cell-type-specific expression pattern. Protein-DNA interactions in this promoter were identified by dimethyl sulfate in vivo footprinting analysis of NG108-15 cells, expressing endogenous DOR. Complete protection of the putative Sp1 cis-element and partial protection of...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.60.2.331
更新日期:2001-08-01 00:00:00
abstract::To study behavior of activated G(alpha)(s) in living cells, green fluorescent protein (GFP) was inserted within the internal amino acid sequence of G(alpha)(s) to generate a G(alpha)(s)-GFP fusion protein. The fusion protein maintained a bright green fluorescence and was identified by immunoblotting with antibodies ag...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.2.352
更新日期:2002-02-01 00:00:00
abstract::In this study, the expression of CYP26 is examined in relation to retinoid-induced mucosecretory differentiation in human tracheobronchial epithelial (HTBE) cells and compared with that in human lung carcinoma cell lines. In HTBE cells, retinoic acid (RA) inhibits squamous differentiation and induces mucous cell diffe...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.3.483
更新日期:2000-09-01 00:00:00
abstract::Depending on their primary structure, the 28 mammalian transient receptor potential (TRP) cation channels identified so far can be sorted into 6 subfamilies: TRPC ("Canonical"), TRPV ("Vanilloid"), TRPM ("Melastatin"), TRPP ("Polycystin"), TRPML ("Mucolipin"), and TRPA ("Ankyrin"). The TRPV subfamily (vanilloid recept...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.109.055624
更新日期:2009-06-01 00:00:00
abstract::We have identified alpha 2-adrenergic receptors on human erythroleukemia (HEL) cells, a suspension-grown cell line related to human platelets. properties of receptors were assessed in intact cells by binding of the antagonist [3H]yohimbine and by inhibition of cAMP accumulation. [3H]Yohimbine labeled 5900 +/- 2100 rec...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-08-01 00:00:00
abstract::Interleukin 6 (IL-6), which is elevated in patients with congestive heart failure and acts as both a chronic marker of inflammation and an acute-phase reactant, is associated with myocardial damage. Circulating levels of arginine vasopressin (AVP) are elevated during cardiac stress and could be a factor for cardiac in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.107698
更新日期:2017-09-01 00:00:00
abstract::Increasing data indicate that brain endocannabinoid system plays a role in the effects of antidepressant medications. Here we examined the effect of in vivo exposure to the selective serotonin uptake inhibitor fluoxetine on cannabinoid type 1 (CB(1)) receptor density and functionality in the rat prefrontal cortex (PFC...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.060079
更新日期:2010-03-01 00:00:00
abstract::Ubiquitination plays a crucial role in regulating protein turnover. Here we show that ubiquitination regulates the stability of the MDR1 gene product, P-glycoprotein, thereby affecting the functions of this membrane transporter that mediates multidrug resistance. We found that P-glycoprotein was constitutively ubiquit...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.001966
更新日期:2004-09-01 00:00:00
abstract::Using [3H]leukotriene C4 (LTC4) and radioligand-binding techniques, specific leukotriene C4 binding sites have been identified in membranes derived from guinea pig ventricular myocardium. High performance liquid chromatography analyses indicated that, in the presence of the gamma-glutamyl transpeptidase inhibitor L-se...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-02-01 00:00:00
abstract::In the present study we have investigated the capacity of various compounds sterically related to indolo[3,2-b]carbazole to inhibit specific 2,3,7,8-tetrachloro[1,6-3H]dibenzo-p-dioxin binding in rat liver cytosol, as analyzed by electrofocusing in polyacrylamide gels. When the two nitrogen atoms of indolo[3,2-b]carba...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-08-01 00:00:00
abstract::Recently, several classes of compounds have been shown to be potent, selective, and specific inhibitors of human immunodeficiency virus type 1 replication in vitro. These include the tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) and the 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (H...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-05-01 00:00:00
abstract::The thiazolidinediones are a class of antidiabetic compounds that increase the sensitivity of target tissues to insulin. An earlier study has shown that these compounds enhance the insulin-stimulated differentiation of 3T3-L1 cells and up-regulate expression of differentiation-dependent genes. We have observed that th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
abstract::The carbonic anhydrase (CA) isozyme (IV) in microsomes is thought to have a dominant role in secretory processes. Using microsomes from bovine kidney and lung (which had the same activity), we have measured the Km and kcat for CO2 hydration and compared these numbers with those for CA I (red blood cells and gut), CA I...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::Westernization of dietary habits increases lipid intake and is responsible for increased numbers of patients with atherosclerotic diseases. Niemann-Pick C1-Like 1 (NPC1L1)-a cholesterol importer-plays a crucial role in dietary cholesterol absorption in the intestine and is closely associated with several lipid-related...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.115840
更新日期:2019-07-01 00:00:00
abstract::Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT are still under investiga...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.116137
更新日期:2019-08-01 00:00:00
abstract::Many cellular signaling pathways share regulation by protein phosphatase-2A (PP2A), a widely expressed serine/threonine phosphatase, and the heterotrimeric G protein Galpha(12). PP2A activity is altered in carcinogenesis and in some neurodegenerative diseases. We have identified binding of Galpha(12) with the Aalpha s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.033555
更新日期:2007-05-01 00:00:00
abstract::Studies in vertebrate neuromuscular synapses have revealed previously that ATP, via P2Y receptors, plays a critical role in regulating postsynaptic gene expressions. An equivalent regulatory role of ATP and its P2Y receptors would not necessarily be expected for the very different situation of the brain synapses, but ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.066506
更新日期:2010-12-01 00:00:00
abstract::Very few antagonists have been identified for the human pregnane X receptor (PXR). These molecules may be of use for modulating the effects of therapeutic drugs, which are potent agonists for this receptor (e.g., some anticancer compounds and macrolide antibiotics), with subsequent effects on transcriptional regulatio...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.049437
更新日期:2008-09-01 00:00:00
abstract::The role of mitogen-activated protein kinase signaling and the transcription factor c-Jun in epidermal growth factor (EGF)-induced expression of 12-lipoxygenase in human epidermoid carcinoma A431 cells was studied. EGF increased the activation of extracellular signal-regulated kinase (ERK) and c-Jun amino terminal kin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2000-01-01 00:00:00
abstract::Several structurally related series of folate analogs were studied as substrates for mouse liver folylpolyglutamate synthetase (FPGS). A comparison of the kinetics of the interaction of this enzyme with folate analogs that contained the quinazoline ring in place of the pteridine ring with those of the analogous pterid...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-11-01 00:00:00
abstract::There are now several examples of single G protein-coupled receptors to which binding of specific agonists causes differential effects on the associated signaling pathways. The dopamine D(2) receptor is of special importance because the selective activation of functional pathways has been shown both in vitro and in si...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.66.1.97
更新日期:2004-07-01 00:00:00
abstract::Although nonsteroidal anti-inflammatory drugs (NSAIDs) are used as cancer chemopreventative agents, their mechanism is unclear because NSAIDs have cyclooxygenase-independent actions. We investigated an alternative target for NSAIDs, peroxisome proliferator-activated receptor-gamma (PPARgamma), activation of which decr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.1.7
更新日期:2002-01-01 00:00:00
abstract::Several reports have been published recently demonstrating a beneficial effect of epidermal growth factor receptor (EGFR) inhibitors in improving pathologic and behavioral conditions in neurodegenerative diseases (NDDs) such as Alzheimer's disease and Amyotrophic Lateral Sclerosis (ALS) as well as the brain and spinal...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.120.119909
更新日期:2020-07-01 00:00:00
abstract::Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term pote...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.082891
更新日期:2013-04-01 00:00:00
abstract::Inhibition of multidrug resistance protein 1 (MRP1) mediated cytostatic drug efflux might be useful in the treatment of drug resistant tumors. Because the glutathione (GSH) conjugate of ethacrynic acid (EA), GS-EA, is a good substrate of MRP1, GS-EA derivatives are expected to be good inhibitors of MRP1. To study stru...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.5.1160
更新日期:2002-11-01 00:00:00
abstract::NAD(P):quinone acceptor oxidoreductase (quinone reductase) (DT-diaphorase, EC 1.6.99.2) is involved in the process of reductive activation of cytotoxic antitumor quinones and nitrobenzenes. In this study, we initially examined the relative abilities of mouse, rat, and human quinone reductases to reduce two prodrugs, C...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-05-01 00:00:00
abstract::The antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was found to be an efficient substrate for recombinant Drosophila melanogaster-deoxyribonucleoside kinase with a K(m) of 4.5 microM and a V(max) of 400 nmol/microg protein/h compared with 1.3 microM and 62.5 nmol/microg protein/h, respectively, for the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.57.4.811
更新日期:2000-04-01 00:00:00
abstract::Low-density lipoprotein (LDL) is known to be a mitogenic factor for vascular smooth muscle cells (VSMCs), fibroblasts, and endothelial cells. In the current study, we describe possible intracellular mechanisms by which LDL elicits its mitogenic effects. Stimulation of VSMCs with LDL resulted in a pertussis-toxin (PTX)...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.3.389
更新日期:1997-09-01 00:00:00