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Title 

KRIBB11 iInhibits HSP70 synthesis through inhibition of heat shock factor 1 function by impairing the recruitment of positive transcription elongation factor b to the hsp70 promoter

 

KRIBB11은 p-TEFb결합해 hsp70 promoter recruiting 저해해 HSP70 발현 억제

Authors 

Y J YunJoo Ae KimK D ShinDae Seop ShinYoung Min HanYu Jin LeeJ S LeeByoung-Mog KwonDong Cho Han

Publisher 

American Society for Biochemistry and Molecular Biology

Issue Date 

2011

Citation 

Journal of Biological Chemistry, vol. 286, no. 3, pp. 1737-1747

Keywords 

ApoptosisBody weightCancer therapyChromatin immunoprecipitation analysisDownstream targetGrowth arrestHeat shock proteinHeat-shockHeat-shock factor 1ImmunoblottingIn-controlIn-vitroIndazoleInhibition of tumor growthIntraperitonealLuciferase activitiesNitropyridineNude micePoly polymerasePositive transcription elongation factor bSynthetic chemicalsTarget proteinsTumor tissues

Abstract 

Heat shock factor 1 (HSF1) is the master switch for heat shock protein (HSP) expression in eukaryotes. A synthetic chemical library was screened to identify inhibitors of HSF1 using a luciferase reporter under the control of a heat shock element. A compound named KRIBB11 (N2-(1H-indazole-5-yl)- N6-methyl-3-nitropyridine-2,6-diamine) was identified for its activity in abolishing the heat shock-induced luciferase activity with an IC50 of 1.2 μmol/liter. When the cells were exposed to heat shock in the presence of KRIBB11, the induction of HSF1 downstream target proteins such as HSP27 and HSP70 was blocked. In addition, treatment of HCT-116 cells with KRIBB11 induced growth arrest and apoptosis. Markers of apoptosis, such as cleaved poly(ADPribose) polymerase, were detected after KRIBB11 treatment. Biotinyl-KRIBB11 was synthesized as an affinity probe for the identification of KRIBB11 target proteins. Using affinity chromatography and competition assays, KRIBB11 was shown to associate with HSF1 in vitro. Chromatin immunoprecipitation analysis showed that KRIBB11 inhibited HSF1-dependent recruitment of p-TEFb (positive transcription elongation factor b) to the hsp70 promoter. Finally, intraperitoneal treatment of nude mice with KRIBB11 at 50 mg/kg resulted in a 47.4% (p < 0.05) inhibition of tumor growth without body weight loss. Immunoblotting assays showed that the expression of HSP70 was lower in KRIBB11-treated tumor tissue than in control tissues. Because HSPs are expressed at high levels in a wide range of tumors, these results strengthen the rationale for targeting HSF1 in cancer therapy.

ISSN 

0021-9258

Link 

http://dx.doi.org/10.1074/jbc.M110.179440

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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