The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells

Wu, Dan; Tao, Xuanyu; Chen, Zhipeng; Han, Jianting; Jia, Wenhao; Zhu, Ning; Li, Xiangkai; Wang, Zhiping; He, Yong‐Xing

doi:10.1016/j.jhazmat.2015.12.045

Cited by 27 publications

(11 citation statements)

References 36 publications

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“…Intrinsic fluorescence quenching assay. The interactions between the PhlH protein and different compounds and the dissociation constant (K d ) of those compounds to PhlH were determined by tryptophan fluorescence titration, as described previously (49). Several different concentrations of compounds and 2 M PhlH protein were prepared in Tris buffer (pH 8.0).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Regulator PhlH Modulates 2,4-Diacetylphloroglucinol Biosynthesis in Response to the Biosynthetic Intermediate and End Product

Yan

Yang

Zhao

et al. 2017

Appl Environ Microbiol

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Certain strains of biocontrol bacterium produce the secondary metabolite 2,4-diacetylphloroglucinol (2,4-DAPG) to antagonize soilborne phytopathogens in the rhizosphere. The gene cluster responsible for the biosynthesis of 2,4-DAPG is named and it is still unclear how the pathway-specific regulator within this gene cluster regulates the metabolism of 2,4-DAPG. Here, we found that PhlH in strain 2P24 represses the expression of the gene encoding the 2,4-DAPG hydrolase by binding to a sequence motif overlapping with the -35 site recognized by σ factors. Through biochemical screening of PhlH ligands we identified the end product 2,4-DAPG and its biosynthetic intermediate monoacetylphloroglucinol (MAPG), which can act as signaling molecules to modulate the binding of PhlH to the target sequence and activate the expression of Comparison of 2,4-DAPG production between the Δ, Δ, and Δ mutants confirmed that and impose negative feedback regulation over 2,4-DAPG biosynthesis. It was further demonstrated that the 2,4-DAPG degradation catalyzed by PhlG plays an insignificant role in 2,4-DAPG tolerance but contributes to bacterial growth advantages under carbon/nitrogen starvation conditions. Taken together, our data suggest that by monitoring and down-tuning levels of 2,4-DAPG, the genes could dynamically modulate the metabolic loads attributed to 2,4-DAPG production and potentially contribute to rhizosphere adaptation. 2,4-DAPG, which is synthesized by biocontrol pseudomonad bacteria, is a broad-spectrum antibiotic against bacteria, fungi, oomycetes, and nematodes and plays an important role in suppressing soilborne plant pathogens. Although most of the genes in the 2,4-DAPG biosynthetic gene cluster () have been characterized, it is still not clear how the pathway-specific regulator is involved in 2,4-DAPG metabolism. This work revealed the role of PhlH in modulating 2,4-DAPG levels by controlling the expression of 2,4-DAPG hydrolase PhlG in response to 2,4-DAPG and MAPG. Since 2,4-DAPG biosynthesis imposes a metabolic burden on biocontrol pseudomonads, it is expected that the fine regulation of by PhlH offers a way to dynamically modulate the metabolic loads attributed to 2,4-DAPG production.

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Section: Methodsmentioning

confidence: 99%

Transcriptional Regulator PhlH Modulates 2,4-Diacetylphloroglucinol Biosynthesis in Response to the Biosynthetic Intermediate and End Product

Yan

Yang

Zhao

et al. 2017

Appl Environ Microbiol

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“…Second, the entire system was optimized using the first step method without any constraints. Subsequently, the entire system was heated gradually in the NVT ensemble from 0 to 300 K over 400 ps, with a weak restraint (k = 5 kcal mol 21 Å 22 ) for the complex (Wu et al, 2016). The final coordinates, obtained after the temperature equilibration simulation, were used for a 120-ns MD simulation, during which the temperature was kept by the Langevin thermostat with a collision frequency of 2 ps 21 .…”

Section: Simulation Analysismentioning

confidence: 99%

Scanning for New BRI1 Mutations via TILLING Analysis

et al. 2017

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The identification and characterization of a mutational spectrum for a specific protein can help to elucidate its detailed cellular functions. BRASSINOSTEROID INSENSITIVE1 (BRI1), a multidomain transmembrane receptor-like kinase, is a major receptor of brassinosteroids in Arabidopsis (). Within the last two decades, over 20 different mutant alleles have been identified, which helped to determine the significance of each domain within BRI1. To further understand the molecular mechanisms of BRI1, we tried to identify additional alleles via targeted induced local lesions in genomes. Here, we report our identification of 83 new point mutations in, including nine mutations that exhibit an allelic series of typical phenotypes, from subtle to severe morphological alterations. We carried out biochemicalanalyses to investigate possible mechanisms of these mutations in affecting brassinosteroid signaling. A number of interesting mutations have been isolated via this study. For example, , the only weak allele identified so far with a mutation in the activation loop, showed reduced autophosphorylation activity., a subtle allele with a mutation in the extracellular portion, disrupts the interaction of BRI1 with its ligand brassinolide and coreceptor BRI1-ASSOCIATED RECEPTOR KINASE1. , with a mutation in the extracellular portion, is a subtle defective mutant. Surprisingly, root inhibition analysis indicated that it is largely insensitive to exogenous brassinolide treatment. In this study, we found that possesses kinase activity in vivo, clarifying a previous report arguing that kinase activity may not be necessary for the function of BRI1. These data provide additional insights into our understanding of the early events in the brassinosteroid signaling pathway.

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“…The real-time quantitative reverse transcription PCR (qRT-PCR) was performed by SYBR Premix Ex TapTM II (TaKaRa Biotechnology, Dalian, China) and the assay was carried out in triplicate on a CFX96™ Real-Time system (Bio-Rad, Hercules, CA). The designs of primer sequences referred our previous work [ 27 ]. All reactions were performed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…The FK1 domain of FKBP51 was expressed and purified as previously described [ 27 ]. Namely the sequence encoding FK1 domain was codon-optimized, synthesized and cloned into a pET28b-derived vector.…”

Section: Methodsmentioning

confidence: 99%

“…The immunophilin FKBP51 and FKBP52 act as synergistic chaperone (co-chaperone), together with Hsp90 help correct folding of AR, which are necessary for AR activation [ [23] , [24] , [25] ]. It has been reported that FKBP51 promoted the activity of AR and enhanced the ability of AR to bind androgens, leading to upregulation expression of downstream genes and finally promote proliferation of prostate cancer cells [ 26 , 27 ]. Moreover, Shang et al [ 28 ] demonstrated that FKBP51 is regulated by AR-V7 and interacts with the AKT signaling pathway and NF-кB signaling to inhibit apoptosis of prostate cancer cells which finally promote the formation of CRPC.…”

Section: Introductionmentioning

confidence: 99%

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Rapamycin inhibits AR signaling pathway in prostate cancer by interacting with the FK1 domain of FKBP51

Zhang

et al. 2020

Biochemistry and Biophysics Reports

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Reactivation of the androgen receptor signaling pathway in the emasculated environment is the main reason for the occurrence of castration-resistant prostate cancer (CRPC). The immunophilin FKBP51, as a co-chaperone protein, together with Hsp90 help the correct folding of AR. Rapamycin is a known small-molecule inhibitor of FKBP51, but its effect on the FKBP51/AR signaling pathway is not clear. In this study, the interaction mechanism between FKBP51 and rapamycin was investigated using steady-state fluorescence quenching, X-ray crystallization, MTT assay, and qRT-PCR. Steady-state fluorescence quenching assay showed that rapamycin could interact with FKBP51. The crystal of the rapamycin-FKBP51 complex indicated that rapamycin occupies the hydrophobic binding pocket of FK1 domain which is vital for AR activity. The residues involving rapamycin binding are mainly hydrophobic and may overlap with the AR interaction site. Further assays showed that rapamycin could inhibit the androgen-dependent growth of human prostate cancer cells by down-regulating the expression levels of AR activated downstream genes. Taken together, our study demonstrates that rapamycin suppresses AR signaling pathway by interfering with the interaction between AR and FKBP51. The results of this study not only can provide useful information about the interaction mechanism between rapamycin and FKBP51, but also can provide new clues for the treatment of prostate cancer and castration-resistant prostate cancer.

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The environmental endocrine disruptor p-nitrophenol interacts with FKBP51, a positive regulator of androgen receptor and inhibits androgen receptor signaling in human cells

Cited by 27 publications

References 36 publications

Transcriptional Regulator PhlH Modulates 2,4-Diacetylphloroglucinol Biosynthesis in Response to the Biosynthetic Intermediate and End Product

Transcriptional Regulator PhlH Modulates 2,4-Diacetylphloroglucinol Biosynthesis in Response to the Biosynthetic Intermediate and End Product

Scanning for New BRI1 Mutations via TILLING Analysis

Rapamycin inhibits AR signaling pathway in prostate cancer by interacting with the FK1 domain of FKBP51

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