ABCC1 p.Asp281Gly
| Predicted by SNAP2: | A: N (78%), C: N (66%), E: N (82%), F: N (53%), G: N (61%), H: N (61%), I: N (57%), K: N (78%), L: N (57%), M: N (61%), N: N (72%), P: N (57%), Q: N (87%), R: N (66%), S: N (87%), T: N (82%), V: N (66%), W: D (63%), Y: D (59%), |
| Predicted by PROVEAN: | A: N, C: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Mutant p53 cooperates with ETS and selectively up-... J Biol Chem. 2001 Oct 19;276(42):39359-67. Epub 2001 Aug 1. Sampath J, Sun D, Kidd VJ, Grenet J, Gandhi A, Shapiro LH, Wang Q, Zambetti GP, Schuetz JD
Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 not MRP1.
J Biol Chem. 2001 Oct 19;276(42):39359-67. Epub 2001 Aug 1., 2001-10-19 [PMID:11483599]
Abstract [show]
The most frequently expressed drug resistance genes, MDR1 and MRP1, occur in human tumors with mutant p53. However, it was unknown if mutant p53 transcriptionally regulated both MDR1 and MRP1. We demonstrated that mutant p53 did not activate either the MRP1 promoter or the endogenous gene. In contrast, mutant p53 strongly up-regulated the MDR1 promoter and expression of the endogenous MDR1 gene. Notably, cells that expressed either a transcriptionally inactive mutant p53 or the empty vector showed no endogenous MDR1 up-regulation. Transcriptional activation of the MDR1 promoter by mutant p53 required an Ets binding site, and mutant p53 and Ets-1 synergistically activated MDR1 transcription. Biochemical analysis revealed that Ets-1 interacted exclusively with mutant p53s in vivo but not with wild-type p53. These findings are the first to demonstrate the induction of endogenous MDR1 by mutant p53 and provide insight into the mechanism.
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No. Sentence Comment
35 QuickChange site-directed mutagenesis (Stratagene, La Jolla, CA) was performed on the CMV-p53 plasmid with two oligonucleotide primers designed to change amino acid 281 from aspartate to glycine, and plasmid DNA was sequenced to identify the clones with the desired aspartate to glycine mutation.
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ABCC1 p.Asp281Gly 11483599:35:165
status: NEW52 The hot-spot MT p53 expression vectors have been described previously (V143A, R175H, R248W, R273H, and D281G) (13) and were provided kindly by Dr. Arnold J. Levine (Rockefeller University, New York).
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ABCC1 p.Asp281Gly 11483599:52:103
status: NEW98 Because it is unknown if p53-mediated repression of the human MDR1 promoter (7, 24) and its activation by MT p53 are mediated by distinct cis-elements, we used a series of MDR1 promoter deletion constructs to assess both repression by wt p53 and activation by the MT p53 containing an aspartate to glycine at amino acid 281 in p53 (p53-281).
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ABCC1 p.Asp281Gly 11483599:98:285
status: NEW235 For instance, heat shock 70 binds p53- 143A and R175H, but not R248W, R273H, or D281G (14, 36).
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ABCC1 p.Asp281Gly 11483599:235:80
status: NEW[hide] Modulation of multidrug resistance-associated prot... Cancer Chemother Pharmacol. 2003 Feb;51(2):161-6. Epub 2002 Dec 3. Tsang WP, Chau SP, Fung KP, Kong SK, Kwok TT
Modulation of multidrug resistance-associated protein 1 (MRP1) by p53 mutant in Saos-2 cells.
Cancer Chemother Pharmacol. 2003 Feb;51(2):161-6. Epub 2002 Dec 3., [PMID:12647018]
Abstract [show]
The p53 tumor suppressor gene is one of the most frequently mutated genes in human cancer and the mutation is correlated with a poor prognosis in cancer therapy. Upregulation of multidrug resistance-associated protein 1 (MRP1) and increase in drug resistance have been found to be induced by p53 mutation. Human osteosarcoma Saos-2 cells, a p53-null cell line, was transfected with p53 with mutations at codon 143 (V to A), 175 (R to H), 248 (R to W), 273 (R to H) and 281 (D to G). Among the different transfectants, overexpression (about 42-fold) of MRP1 was detected in p53-R175H cells. Furthermore, the p53-R175H cells were 2.5-fold more resistant to doxorubicin (DOX) and had a 4-fold greater DOX efflux rate than the control cells 1 h after DOX treatment. Transfection with antisense MRP1 oligonucleotides demonstrated a DOX sensitization effect (about 2-fold) in p53-R175H transfectants but not in control cells. In addition, transfection with antisense p53 oligonucleotides greatly suppressed MRP1 expression and reversed DOX resistance in p53-R175H cells but had no effect in control cells. The results suggested that p53-R175H might induce MRP1 expression and DOX resistance in cells.
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No. Sentence Comment
27 Human osteosarcoma Saos-2 cells, a p53-null cell line, were transfected with five different p53 mutants (V143A, R175H, D248W, R273H and D281G).
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ABCC1 p.Asp281Gly 12647018:27:136
status: NEW[hide] Transcriptional suppression of multidrug resistanc... Cancer Res. 1998 Dec 15;58(24):5762-9. Wang Q, Beck WT
Transcriptional suppression of multidrug resistance-associated protein (MRP) gene expression by wild-type p53.
Cancer Res. 1998 Dec 15;58(24):5762-9., [PMID:9865734]
Abstract [show]
Multidrug resistance is a major obstacle to the success of cancer chemotherapy. The multidrug resistance-associated protein (MRP) has been shown to confer multidrug resistance. To study MRP gene expression at the transcriptional level, we have fused the MRP gene promoter with the luciferase reporter gene and studied its regulation. Cotransfection of MRP promoter constructs with p53 expression plasmids in p53-null human H1299 and mouse (10)1 cells demonstrated that the wild-type (wt) p53 markedly suppressed MRP promoter activity, whereas mutant p53 had little inhibitory effect. Transfections using 5' deletion mutant constructs of the MRP promoter showed that inhibition of the promoter activity by wt p53 mainly resided in the region from -91 to +103 bp, where several Sp1 transcription factor binding sites are localized. Cotransfection of the MRP promoter into Drosophila SL2 cells with an Sp1 expression vector increased the promoter activity in a dose-related manner up to approximately 200-fold. The stimulation of MRP promoter activity by Sp1 was attenuated by the cotransfection of a wt p53-expression plasmid. Furthermore, we have determined that endogenous MRP mRNA levels were down-regulated by restoration of wt p53-expression in a human lung cancer cell line. The relevance of MRP regulation in drug resistance was studied in a drug-resistant cell line, CEM/VM-1-5, that is approximately 140-fold more resistant to the epipodophyllotoxin, teniposide (VM-26), than the parental CEM cells. CEM/VM-1-5 cells express a much higher amount of MRP mRNA and protein than CEM cells, indicating that the resistant phenotype is at least partly due to increased MRP production. Transient transfection of the promoter constructs revealed that CEM/VM-1-5 cells had higher (7-fold) MRP promoter activity than CEM cells. Cotransfection of a wt p53-expression plasmid caused a reduction of MRP promoter activity in both CEM and CEM/VM-1-5 cells, but the inhibition was more than double in CEM/VM-1-5 cells compared with CEM cells. Our results demonstrated that wt p53 acts as a negative regulator of MRP gene transcription, at least in part by diminishing the effect of a powerful transcription activator Sp1. Therefore, a loss of wt p53 function and/or an increase in Sp1 activity in tumor cells could contribute to an up-regulation of the MRP gene.
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No. Sentence Comment
76 Other vectors expressing a mutant human p53 were similarly con structed: (a) p53-175 is a mutant human p53 cDNA expression plasmid harboring a substitution from arginine to histidine at aa 175: (b) p53-281 has a mutation from aspartic acid to glycine at aa 281; and (c) p53-22/23 has mutations at aa 22 and aa 23.
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ABCC1 p.Asp281Gly 9865734:76:226
status: NEW