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Drug-Target Interaction

Drug

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PubChem ID:544
Structure:
Synonyms:
11118-55-1
15502-74-6
AC1L19H4
Arsenite
Arsenite ions
arsenite(3-)
arsorite
AsO3(3-)
AST
C015001
C06697
CHEBI:29866
CHEMBL1231071
trioxidoarsenate(3-)
trioxoarsenate(3-)
trioxoarsenate(III)
[AsO3](3-)

Target

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Uniprot ID:JUN_MOUSE
Synonyms:
Activator protein 1
AH119
AP1
Jun A
Proto-oncogene c-jun
Transcription factor AP-1
V-jun avian sarcoma virus 17 oncogene homolog
EC-Numbers:-
Organism:Mouse
Mus musculus
PDB IDs:-

Binding Affinities:

Ki: Kd:Ic 50:Ec50/Ic50:
----
----
----

References:

10983895
Inhibition of arsenite-induced apoptosis and AP-1 activity by epigallocatechin-3-gallate and theaflavins.. N Y Chen; W Y Ma; C S Yang; Z Dong (2000) Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer display abstract
Arsenite-induced apoptosis appears to be important in its toxicity and its role in carcinogenesis. Green tea has been used as a traditional Chinese remedy for detoxification of arsenite-caused toxicity. In the present work, we found that tea polyphenols, EGCG and theaflavins, effectively blocked arsenite-induced apoptosis of JB6 cells and inhibited arsenite-induced AP-1 transcription activity and AP-1 DNA binding activity. EGCG and theaflavins potently inhibited arsenite-induced Erks activity, but not p38 kinase activity. PD 98059, an inhibitor of Erks, and DNM-JNK1 blocked arsenite-induced apoptosis, while SB202190, an inhibitor of p38 kinases, or DNM-p38 kinase did not. We conclude that Erks and JNKs may be involved in arsenite-induced apoptosis, and the inhibition of arsenite-induced apoptosis by EGCG and theaflavins may be mediated by a decreased phosphorylation of Erks and JNKs. Furthermore, these results provide a possible mechanism for the detoxification effect of tea on arsenite-induced toxicity.
10983896
Activation of PKC is required for arsenite-induced signal transduction.. N Y Chen; W Y Ma; C Huang; M Ding; Z Dong (2000) Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer display abstract
Trivalent arsenic (arsenite) is a human carcinogen. However, the molecular mechanism of arsenite-induced carcinogenesis is still not well understood. In this study, we found that arsenite induced translocation of PKCepsilon, PKCdelta, and PKCalpha from cytosol to membranes. Rottlerin, a selective inhibitor for PKCdelta, and safingol, a specific inhibitor for PKCalpha, both markedly inhibited arsenite-induced AP-1 activity. These inhibitory effects by rottlerin and safingol appeared to be dose dependent. Arsenite-induced phosphorylation of Erks was inhibited by rottlerin, while safingol inhibited arsenite-induced phosphorylation of JNKs and p38 kinases. Dominant negative mutant transfectant of PKCepsilon markedly blocked arsenite-induced AP-1 activity and the phosphorylation of Erks, JNKs, and p38 kinases. These data demonstrate that PKCdelta, PKCepsilon, and PKCalpha mediate arsenite-induced AP-1 activation in JB6 cells through different MAP kinase (Erks, JNKs, and p38 kinases) pathways.
14516795
Hydrogen peroxide mediates arsenite activation of p70(s6k) and extracellular signal-regulated kinase.. Dong Keun Jung; Gyu-Un Bae; Yong Kee Kim; Seung-Hee Han; Wahn Soo Choi; Hyeog Kang; Dong Wan Seo; Hoi Young Lee; Eun-Jung Cho; Hyang-Woo Lee; Jeung-Whan Han (2003) Experimental cell research display abstract
To define the mechanism of arsenite-induced tumor promotion, we examined the role of reactive oxygen species (ROS) in the signaling pathways of cells exposed to arsenite. Arsenite treatment resulted in the persistent activation of p70(s6k) and extracellular signal-regulated kinase 1/2 (ERK1/2) which was accompanied by an increase in intracellular ROS production. The predominant produced appeared to be H(2)O(2), because the arsenite-induced increase in dichlorofluorescein (DCF) fluorescence was completely abolished by pretreatment with catalase but not with heat-inactivated catalase. Elimination of H(2)O(2) by catalase or N-acetyl-L-cysteine inhibited the arsenite-induced activation of p70(s6k) and ERK1/2, indicating the possible role of H(2)O(2) in the arsenite activation of the p70(s6k) and the ERK1/2 signaling pathways. A specific inhibitor of p70(s6k), rapamycin, and calcium chelators significantly blocked the activation of p70(s6k) induced by arsenite. While the phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin and LY294002 completely abrogated arsenite activation of p70(s6k), ERK1/2 activation by arsenite was not affected by these inhibitors, indicating that H(2)O(2) might act as an upstream molecule of PI3K as well as ERK1/2. Consistent with these results, none of the inhibitors impaired H(2)O(2) production by arsenite. DNA binding activity of AP-1, downstream of ERK1/2, was also inhibited by catalase, N-acetyl-L-cysteine, and the MEK inhibitor PD98059, which significantly blocked arsenite activation of ERK1/2. Taken together, these studies provide insight into mechanisms of arsenite-induced tumor promotion and suggest that H(2)O(2) plays a critical role in tumor promotion by arsenite through activation of the ERK1/2 and p70(s6k) signaling pathways.