Physiological Role for the Cochaperone FKBP52 in Androgen Receptor Signaling

Cheung‐Flynn, Joyce; Prapapanich, Viravan; Cox, Marc B.; Riggs, Daniel L.; Suárez‐Quian, Carlos A.; Smith, David F.

doi:10.1210/me.2005-0071

Cited by 192 publications

(215 citation statements)

References 41 publications

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“…C57BL/6/129 and CD1 Fkbp52 −/− mice (9,30) and C57BL6/129 Pgr −/− mice (31) were used in this study. FKBP52 and PR mutant mice were originally obtained from David Smith (Mayo Clinic, Scottsdale, AZ) and Bert O'Malley (Baylor College of Medicine, Houston, TX), respectively.…”

Section: Methodsmentioning

confidence: 99%

Uterine FK506-binding protein 52 (FKBP52)–peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress

Hirota

Acar

Tranguch

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Immunophilin FK506-binding protein 52 (FKBP52) is a cochaperone that binds to the progesterone receptor (PR) to optimize progesterone (P 4 )-PR signaling. We recently showed that Fkbp52-deficient (Fkbp52 −/− ) mice have reduced uterine PR responsiveness and implantation failure which is rescued by excess P 4 supplementation in a genetic background-dependent manner. This finding led us to hypothesize that FKBP52 has functions in addition to optimizing PR activity. Using proteomics analysis, we found that uterine levels of peroxiredoxin-6 (PRDX6), a unique antioxidant, are significantly lower in Fkbp52 −/− mice than in WT and PR-null (Pgr −/− ) mice. We also found that Fkbp52 −/− mice with reduced uterine PRDX6 levels are susceptible to paraquat-induced oxidative stress (OS), leading to implantation failure even with P 4 supplementation. The same dose of paraquat did not interfere with implantation in WT mice. Moreover, treatment with antioxidants α-tocopherol and N-acetylcysteine (NAC) attenuated paraquat-induced implantation failure in P 4 -treated Fkbp52 −/− mice. Functional analyses using mouse embryonic fibroblasts show that Fkbp52 deficiency associated with reduced PRDX6 levels promotes H 2 O 2 -induced cell death, which is reversed by the addition of NAC or by forced expression of PRDX6, suggesting that Fkbp52 deficiency diminishes the threshold against OS by reducing PRDX6 levels. These findings provide evidence that heightened uterine OS in Fkbp52 −/− females with reduced PRDX6 levels induces implantation failure even in the presence of excess P 4 . This study shows that FKBP52-PRDX6 signaling protects pregnancy from overt OS.embryo implantation | mouse | uterus

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Section: Methodsmentioning

confidence: 99%

Uterine FK506-binding protein 52 (FKBP52)–peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress

Hirota

Acar

Tranguch

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…167 The recent creation of the Fkbp52 −/− mouse for the first time has demonstrated that the immunophilin class of cochaper-one proteins play a significant role in regulating the functional properties of certain nuclear receptors, like the PR 168 and androgen receptor. 169 The loss of the FKBP52 protein in the null mouse line results in both male and female infertility due to severe deficiencies in androgen or progesterone responsiveness, respectively.…”

Section: The Hepatitis B Virus X-associated Proteinmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression

Beischlag

Morales

Hollingshead

et al. 2008

Crit Rev Eukar Gene Expr

632

587

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The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of a diverse set of genes. The toxicity of the potent AhR ligand 2,3,7,8-tetrachlorodibenzop-dioxin is almost exclusively mediated through this receptor. However, the key alterations in gene expression that mediate toxicity are poorly understood. It has been established through characterization of AhR-null mice that the AhR has a required physiological function, yet how endogenous mediators regulate this orphan receptor remains to be established. A picture as to how the AhR/ARNT heterodimer actually mediates gene transcription is starting to emerge. The AhR/ ARNT complex can alter transcription both by binding to its cognate response element and through tethering to other transcription factors. In addition, many of the coregulatory proteins necessary for AhR-mediated transcription have been identified. Cross talk between the estrogen receptor and the AhR at the promoter of target genes appears to be an important mode of regulation. Inflammatory signaling pathways and the AhR also appear to be another important site of cross talk at the level of transcription. A major focus of this review is to highlight experimental efforts to characterize nonclassical mechanisms of AhR-mediated modulation of gene transcription.

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“…Additionally, it is not infrequent for mammalian young to be born with ambiguous external genitalia [22,23]. Therefore, FISH could be an alternative to PCR to analyzing the sex chromosome complement, if the methodology could be routinely applied at a low cost.…”

Section: Introductionmentioning

confidence: 99%

Fluorescent in situ hybridization for sex chromosome determination before and after fertilization in mice

2007

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In mice, the relative numbers of male and female pups per litter not only can vary but can probably change over the course of pregnancy in response to numerous environmental and physiological factors. As such, a technique is required to determine gender at several developmental stages. Here we describe a robust and accurate fluorescent in situ hybridization (FISH) procedure for determining chromosomal sex that can be applied with minimal modification to sperm, pre-and post-implantation conceptuses and recovered dead post-natal pups. Sperm was prepared for FISH analysis y using a modified microwave decondensation-denaturation technique. Preimplantation conceptuses (0.5 dpc) were cultured to the morula stage before sexing. They were then acid-treated to remove the zona pellucida. Tissue homogenates from postimplantational conceptuses (8.5 dpc) and stillborn pups were fixed to pre-etched slides. Specimens were hybridized with identical, commercially available DNA probes for the X (FITC) and Y (Cy3) chromosomes. Sperm ratios met the expected value of 0.5 when determined by using XY FISH. Preimplantation conceptuses pre-treated with pepsin yielded distinct fluorescence of X and Y chromosomes in morulae, whereas microwave decondensation resulted in loss of conceptuses from the slide. Both 4.0 and 8.5 dpc conceptuses displayed mean sex ratios of 0.5. Post-natal FISH analysis allowed gender identification of pups that could not be sexed due to developmental abnormalities or partial cannibalism. FISH analysis of sperm and of multiple conceptuses or post-natal tissue provided a cost-effective, accurate alternative to PCR-based sex determination.

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Physiological Role for the Cochaperone FKBP52 in Androgen Receptor Signaling

Cited by 192 publications

References 41 publications

Uterine FK506-binding protein 52 (FKBP52)–peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress

Uterine FK506-binding protein 52 (FKBP52)–peroxiredoxin-6 (PRDX6) signaling protects pregnancy from overt oxidative stress

The Aryl Hydrocarbon Receptor Complex and the Control of Gene Expression

Fluorescent in situ hybridization for sex chromosome determination before and after fertilization in mice

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