| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T11253 | ||||
| Target Name | mRNA of Heatshock 27 kDa protein | ||||
| Target Type | Discontinued |
||||
| Drug Potency against Target | SB-242235 | Drug Info | IC50 = 160 nM | [529583] | |
| Action against Disease Model | OGX-427 | H uMan KU-7 bladder t uMour cells were treated with OGX-427 or a mismatch (MM) control oligodeoxynucleotide (ODN) in vitro and were assessed for HSP27 expression, proliferation and apoptosis. In vitro, OGX-427 significantly decreased HSP27 protein levels and cellular viability. While naked OGX-427 showed only a trend in t uMour suppression compared with MM ODN, OGX-427 complexed with chitosan significantly inhibited orthotopic t uMour growth. The chitosan preparation induced some haematuria compared to naked ASO, but this formulation had superior tissue uptake of oligonucleotides and suppressed HSP27 tissue levels by 75%. | [552502] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | p27 is an atypical t uMor suppressor that can regulate the activity of cyclin-dependent kinases and G(0)-to-S phase transitions. More recent studies reveal that p27 may also exhibit its t uMor-suppressive function through regulating many other essential cellular events. However, the molecular mechanisms underlying these anticancer effects of p27 are largely unknown. In this study, we found that depletion of p27 expression by either gene knock-out or knockdown approaches resulted in up-regulation of both Hsp27 and Hsp70 expression at mRNA- and promoter-derived transcription as well as protein levels upon arsenite exposure, indicating that p27 provides a negative signal for regulating the expression of Hsp27 and Hsp70. Consistently, arsenite-induced activation of JNK2/c-Jun and HSF-1 pathways was also markedly elevated in p27 knock-out (p27(-/-)) and knockdown (p27 shRNA) cells. Moreover, interference with the expression or function of JNK2, c-Jun, and HSF-1, but not JNK1, led to dramatic inhibition of arsenite-induced Hsp27 and Hsp70 expression. Collectively, our results demonstrate that p27 suppresses Hsp27 and Hsp70 expression at the transcriptional level specifically through JNK2/c-Jun- and HSF-1-dependent pathways upon arsenite exposure, which provides additional important molecular mechanisms for the t uMor-suppressive function of p27 | [529583] | |||
| References | |||||
| Ref 529583 | Bioorg Med Chem Lett. 2008 Aug 1;18(15):4433-7. Epub 2008 Jun 12.Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. | ||||
| Ref 552502 | Origin, structure, and activity in vitro and in vivo of dalbavancin. J Antimicrob Chemother. 2005 Mar;55 Suppl 2:ii15-20. | ||||
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