Abstract:
:Studies of the biochemical mechanisms evoked by conventional treatments for neoplastic diseases point to apoptosis as a key process for elimination of unwanted cells. Although the pathways through which chemotherapeutics promote cell death remain largely unknown, caspase proteases play a central role in the induction of apoptosis in response to a variety of stimuli including tumor necrosis factor, fas ligand, and growth factor deprivation. In this article, we demonstrate the induction of caspase protease activity in MCF7 human breast carcinoma cells exposed to the topoisomerase inhibitor, etoposide. Caspase protease activity was assessed by incubating cell lysates with the known caspase substrates, acetyl-L-aspartic-L-glutamic-L-valyl-L-aspartic acid 4-methyl-7-aminocoumarin or acetyl-L-tyrosyl-L-valyl-L-aspartic acid 4-methyl-7-aminocoumarin. We observed maximal cleavage of acetyl-L-aspartic-L-glutamic-L-valyl-L-aspartic acid 4-methyl-7-aminocoumarin within 6 hr following etoposide addition, a time that precedes cell death. In contrast, acetyl-L-tyrosyl-L-valyl-L-aspartic acid 4-methyl-7-aminocoumarin was resistant to cleavage activity. This substrate cleavage specificity implies that a caspase-3-like protease is activated in response to DNA damage. Consistent with the lysate protease activity, an intracellular marker of caspase activation, poly-ADP ribose polymerase (PARP), was cleaved in a concentration- and time-dependent manner after etoposide-treatment. PARP cleavage followed caspase activation and reached maximum cleavage between 12 and 16 hr. Incubation of the cells with the peptidic caspase inhibitor z-valine-alanine-asparagine-CH2F prevented caspase activation, inhibited PARP cleavage, and inhibited cell death. Thus, etoposide killing of MCF7 cells requires a caspase-3-like protease.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Benjamin CW,Hiebsch RR,Jones DAdoi
10.1124/mol.53.3.446subject
Has Abstractpub_date
1998-03-01 00:00:00pages
446-50issue
3eissn
0026-895Xissn
1521-0111journal_volume
53pub_type
杂志文章abstract::The protease-activated receptors (PAR1 and PAR2) are unusual G protein-coupled receptors that are activated by distinct serine proteases and are coexpressed in many different cell types. Limited recent evidence suggests these closely related receptors regulate different physiological outputs in the same cell, although...
journal_title:Molecular pharmacology
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abstract::A central axiom of ligand-receptor theory is that agonists bind more tightly to active than to inactive receptors. However, measuring agonist affinity in inactive receptors is confounded by concomitant activation. We identified a cysteine substituted mutant γ-aminobutyric acid type A (GABAA) receptor with unique chara...
journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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abstract::The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nit...
journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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journal_title:Molecular pharmacology
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更新日期:1993-02-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-08-01 00:00:00
abstract::Antibodies against synthetic peptides of the D2 dopamine receptor were used, in combination with photoaffinity labeling, to localize the region of ligand binding in the receptor. Specific antibodies to peptide sequences 221-234 and 259-272 and to the carboxyl-terminal peptide 402-415, all corresponding to cytoplasmic ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-11-01 00:00:00
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doi:
更新日期:1989-12-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-03-01 00:00:00
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journal_title:Molecular pharmacology
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doi:
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-04-01 00:00:00
abstract::NS20Y neuroblastoma cells expressing a homogeneous population of D1-dopamine receptors were used in the present study as a model system to investigate the mechanisms of agonist-induced stimulation and desensitization of D1 receptor-coupled adenylyl cyclase activity. Membrane prepared from NS20Y cells showed a pharmaco...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-10-01 00:00:00
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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
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
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更新日期:2014-02-01 00:00:00
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更新日期:1989-09-01 00:00:00