Abstract：
:We have observed that rodent cell lines (mouse, hamster) contain approximately 10 times the levels of dihydrofolate reductase as human cell lines, yet the sensitivity to methotrexate (ED(50)), the folate antagonist that targets this enzyme, is similar. Our previous studies showed that dihydrofolate reductase protein levels increased after methotrexate exposure, and we proposed that this increase was due to the relief of feedback inhibition of translation as a consequence of methotrexate binding to dihydrofolate reductase. In the current report, we show that unlike what was observed in human cells, dihydrofolate reductase (DHFR) levels do not increase in hamster cells after methotrexate exposure. We provide evidence to show that although there are differences in the putative mRNA structure between hamster and human mRNA in the dihydrofolate reductase binding region previously identified, "hamsterization" of this region in human dihydrofolate reductase mRNA did not change the level of the enzyme or its induction by methotrexate. Further experiments showed that human dihydrofolate reductase is a promiscuous enzyme and that it is the difference between the hamster and human dihydrofolate reductase protein, rather than the DHFR mRNA, that determines the response to methotrexate exposure. We also present evidence to suggest that the translational up-regulation of dihydrofolate reductase by methotrexate in tumor cells is an adaptive mechanism that decreases sensitivity to this drug.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Hsieh YC,Skacel NE,Bansal N,Scotto KW,Banerjee D,Bertino JR,Abali EEdoi
10.1124/mol.109.055772subject
Has Abstractpub_date
2009-10-01 00:00:00pages
723-33issue
4eissn
0026-895Xissn
1521-0111pii
mol.109.055772journal_volume
76pub_type
杂志文章abstract：:The fluorogenic sulfhydryl probe 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) (1-50 nM) is used to characterize the functional role and location of highly reactive thiol groups on the ryanodine-sensitive Ca2+ release channel complex [i.e., ryanodine receptors (RyRs)] of skeletal and cardiac junctional...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-02-01 00:00:00
abstract：:In a previous report we described the use of flunitrazepam as a photoaffinity label to monitor the turnover of the gamma-aminobutyric acid/benzodiazepine receptor complex in primary brain and spinal cord cell cultures [Science (Wash. D. C.) 226:857-860 (1984)]. In the present communication we have extended our studies...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1988-09-01 00:00:00
abstract：:Stromal cell-derived factor-1 (SDF-1/CXCL-12) and vascular endothelial growth factor (VEGF), which can be secreted by hypoxic tumors, promote the generation of new blood vessels. These potent angiogenic factors stimulate endothelial cell migration via the activation of Rho GTPases and the phosphatidylinositol 3-kinase...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.060400
更新日期：2010-03-01 00:00:00
abstract：:The two forms of pituitary adenylate cyclase-activating polypeptide, PACAP27 and PACAP38, are two neuropeptide hormones related to the vasoactive intestinal peptide/secretin/ glucagon family of peptides. PACAP receptors that are positively coupled to adenylyl cyclase and phospholipase C have been identified in culture...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-07-01 00:00:00
abstract：:Expression of the angiotensin II type 1 receptor (AT1-R) mRNA in vascular smooth muscle cells (VSMC) is down-regulated by a variety of agonists, including growth factors, agonists of Galphaq protein-coupled receptors, and activators of adenylyl cyclase. To determine whether cAMP-dependent protein kinases (PKA) partici...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.54.3.514
更新日期：1998-09-01 00:00:00
abstract：:The human histamine H(4)-receptor (hH(4)R) possesses high constitutive activity and, like the human H(1)-receptor (hH(1)R), is involved in the pathogenesis of type-I allergic reactions. The study aims were to explore the value of dual H(1)/H(4)R antagonists as antiallergy drugs and to address the question of whether H...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.058651
更新日期：2009-11-01 00:00:00
abstract：:Voltage-gated potassium (Kv) channels regulate many physiological functions and represent important therapeutic targets in the treatment of several clinical disorders. Although some of these channels have been well-characterized, the study of others, such as Kv3 channels, has been hindered because of limited pharmacol...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.105.011064
更新日期：2005-05-01 00:00:00
abstract：:The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) and their class II G protein-coupled receptors VPAC(1), VPAC(2), and PAC(1) play important roles in human physiology. No small molecule modulator has ever been reported for the VIP/PACAP receptors, and ther...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.060137
更新日期：2010-01-01 00:00:00
abstract：:At the vertebrate neuromuscular junction (nmj), ATP is known to be coreleased with acetylcholine from the synaptic vesicles. We have previously shown that the P2Y1 receptor is localized at the nmj. Here, we extend the findings to show that another nucleotide receptor, P2Y2, is also localized there and with P2Y1 jointl...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.003269
更新日期：2004-10-01 00:00:00
abstract：:Dysfunction of p53 and resistance to cancer drugs can arise through mutually exclusive overexpression of MDM2 or MDM4. Cisplatin-resistant cells, however, can demonstrate increased binding of both MDM2 and MDM4 to p53 but in absence of cellular overexpression. Whether MDM2 inhibitors alone can activate p53 in these re...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.119.117564
更新日期：2020-04-01 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：:Metallothioneins (MTs) are low molecular weight, thiol-rich, metal-binding proteins. Auranofin (AF) is a gold compound active in the treatment of rheumatoid arthritis. The effects of AF on regulation of MT gene expression in Chinese hamster ovary cells were studied. AF-resistant cells accumulated substantial amounts o...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1987-01-01 00:00:00
abstract：:The 2,3,7,8-tetrachlorodibenzo-p-dioxin-transformed aryl hydrocarbon receptor (AHR) complex binds to xenobiotic-responsive element (XRE) sequences in the 5' flanking region of the CYP1A1 gene, resulting in initiation of transcription. Both components of the transformed AHR complex [the ligand-binding AHR monomer and t...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-03-01 00:00:00
abstract：:In saturation studies with [3H]dihydromorphine, unlabeled D-Ala2-D-Leu5-enkephalin (1 nM) inhibited the high-affinity binding component far more potently than the lower-affinity one. Similarly, morphine (1 nM) inhibited the higher-affinity binding of 3H-D-Ala2-D-Leu5-enkephalin to a greater extent than its lower-affin...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1984-01-01 00:00:00
abstract：:In the rat isolated optic nerve, nitric oxide (NO) activates soluble guanylyl cyclase (sGC), resulting in a selective accumulation of cGMP in the axons. The axons are also selectively vulnerable to NO toxicity. The experiments initially aimed to determine any causative link between these two effects. It was shown, usi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.61.1.97
更新日期：2002-01-01 00:00:00
abstract：:P2X receptors are trimeric membrane proteins. When they bind extracellular ATP, a conformational change occurs that opens a transmembrane ion channel. The ATP-binding pocket is formed in a cleft between two subunits, and a critical amino acid residue for ATP contact is Lys⁶⁹ (P2X2 numbering). In the present work, we s...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.112.080903
更新日期：2012-10-01 00:00:00
abstract：:Herpes simplex virus type 1 (HSV-1) encodes a thymidine kinase (TK) that markedly differs from mammalian nucleoside kinases in terms of substrate specificity. It recognizes both pyrimidine 2'-deoxynucleosides and a variety of purine nucleoside analogs. Based on a computer modeling study and in an attempt to modify thi...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.58.6.1326
更新日期：2000-12-01 00:00:00
abstract：:Dietary lipids and fat-soluble micronutrients are solubilized in mixed micelles and absorbed in the small intestine. Based on an assumption that cholesterol and other fat-soluble molecules share a number of transport mechanisms and the fact that Niemann-Pick C1-like 1 (NPC1L1) is critical for intestinal cholesterol ab...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.043034
更新日期：2008-07-01 00:00:00
abstract：:Reversible binding of warfarin to defatted serum albumin was studied by equilibrium dialysis at pH 7.4, in a 66 mM sodium phosphate buffer at 37 degrees. The binding isotherm could be described by two stoichiometric binding constants, K1 in the range 141,000 to 192,000 M-1 and K2 at 39,000 to 57,000 M-1. At least two ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1985-02-01 00:00:00
abstract：:Mitochondrial disorders are devastating genetic diseases for which efficacious therapies are still an unmet need. Recent studies report that increased availability of intracellular NAD obtained by inhibition of the NAD-consuming enzyme poly(ADP-ribose) polymerase (PARP)-1 or supplementation with the NAD-precursor nico...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.114.097204
更新日期：2015-06-01 00:00:00
abstract：:Activation of N-methyl-D-aspartate (NMDA) receptors is required for induction of some lasting changes in nervous system structure and function. The cellular mechanisms involved in transducing receptor stimulation into long-lasting changes in cellular activity are unknown. Immediate-early genes (IEGs) have been implica...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-06-01 00:00:00
abstract：:A polyamine component of Agelenopsis aperta spider venom designated FTX is reported to be a selective antagonist of P-type calcium channels in the mammalian brain. Consequently, this component has frequently been used as a pharmacological tool to determine the presence, distribution, and function of P-type channels in...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-10-01 00:00:00
abstract：:Bovine pulmonary artery endothelial (CPAE) cells respond to bradykinin, and it has been suggested that the receptors on these cells do not fall into the normal B1/B2 classification of bradykinin receptors [J. Pharmacol. Exp. Ther. 244:646-649 (1988)]. The present study describes a detailed characterization of the subt...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1995-03-01 00:00:00
abstract：:The lymphocyte potassium channel Kv1.3 is widely regarded as a promising new target for immunosuppression. To identify a potent small-molecule Kv1.3 blocker, we synthesized a series of 5-phenylalkoxypsoralens and tested them by whole-cell patch clamp. The most potent compound of this series, 5-(4-phenylbutoxy)psoralen...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.6.1364
更新日期：2004-06-01 00:00:00
abstract：:Effects of ethanol on the function of Ca(2+)-activated Cl- channels activated by G protein-coupled serotonin (5-hydroxytryptamine, (5-HT)1c) and muscarinic M1 cholinergic receptors were studied in Xenopus oocytes expressing mouse whole-brain mRNA. Ethanol (25-200 mM) inhibited currents evoked by both 5-HT and acetylch...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1994-05-01 00:00:00
abstract：:Equilibrative nucleoside transporters (ENTs) 1 and 2 facilitate nucleoside transport across the blood-testis barrier (BTB). Improving drug entry into the testes with drugs that use endogenous transport pathways may lead to more effective treatments for diseases within the reproductive tract. In this study, CRISPR/CRIS...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/molpharm.120.000169
更新日期：2021-02-01 00:00:00
abstract：:An azido derivative of [3H2](2S, 3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl) methyl)-1-azabicyclo[2.2.2]octon-3-amine (CP-96,345), a potent nonpeptide antagonist of the substance P (SP) (neurokinin-1) receptor, was synthesized and shown to have an affinity for the human SP receptor similar to that of the parent co...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-05-01 00:00:00
abstract：:Glutamatergic synaptic transmitters are cleared from the synaptic cleft through excitatory amino acid transporters (EAATs) that are responsible for recycling glutamate and transporting it into neurons and glial cells. To probe the structural role of the TM4b-4c loop of EAAT1 (Rattus norvegicus), each of the 57 amino a...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.117.111245
更新日期：2018-07-01 00:00:00
abstract：:Cadmium is a dangerous metal distributed widely in the environment. Members of our laboratory recently identified the ZIP8 transporter protein, encoded by the mouse Slc39a8 gene, to be responsible for genetic differences in response to cadmium damage of the testis. Stable retroviral infection of the ZIP8 cDNA in mouse...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.106.024521
更新日期：2006-07-01 00:00:00
abstract：:Peroxisome proliferator-activated receptor δ (PPARδ) has been implicated in vascular pathophysiology. However, its functions in atherogenic changes of the vascular wall have not been fully elucidated. PPARδ activated by GW501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]ph...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.116.104679
更新日期：2016-11-01 00:00:00
