Sayuri Takahashi

Dioxin receptor is a ligand-dependent E3 ubiquitin ligase

Fat-soluble ligands, including sex steroid hormones and environmental toxins, activate ligand-dependent DNA-sequence-specific transcriptional factors that transduce signals through target-gene-selective transcriptional regulation. However, the mechanisms of cellular perception of fat-soluble ligand signals through other target-selective systems remain unclear. The ubiquitin–proteasome system regulates selective protein degradation, in which the E3 ubiquitin ligases determine target specificity. Here we characterize a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which dioxin receptor (AhR) is integrated as a component of a novel cullin 4B ubiquitin ligase complex, CUL4BAhR. Complex assembly and ubiquitin ligase activity of CUL4BAhR in vitro and in vivo are dependent on the AhR ligand. In the CUL4BAhR complex, ligand-activated AhR acts as a substrate-specific adaptor component that targets sex steroid receptors for degradation. Thus, our findings uncover a function for AhR as an atypical component of the ubiquitin ligase complex and demonstrate a non-genomic signalling pathway in which fat-soluble ligands regulate target-protein-selective degradation through a ubiquitin ligase complex.

DNA demethylation in hormone-induced transcriptional derepression

Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood. Here we report that DNA methylation/demethylation is hormonally switched to control transcription of the cytochrome p450 27B1 (CYP27B1) gene. Reflecting vitamin-D-mediated transrepression of the CYP27B1 gene by the negative vitamin D response element (nVDRE), methylation of CpG sites (5mCpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene, induces active demethylation of the 5mCpG sites in this promoter. Biochemical purification of a complex associated with the nVDRE-binding protein (VDIR, also known as TCF3) identified two DNA methyltransferases, DNMT1 and DNMT3B, for methylation of CpG sites, as well as a DNA glycosylase, MBD4 (ref. 10). Protein-kinase-C-phosphorylated MBD4 by parathyroid hormone stimulation promotes incision of methylated DNA through glycosylase activity, and a base-excision repair process seems to complete DNA demethylation in the MBD4-bound promoter. Such parathyroid-hormone-induced DNA demethylation and subsequent transcriptional derepression are impaired in Mbd4-/- mice. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.

The Androgen Receptor in Health and Disease

Androgens play pivotal roles in the regulation of male development and physiological processes, particularly in the male reproductive system. Most biological effects of androgens are mediated by the action of nuclear androgen receptor (AR). AR acts as a master regulator of downstream androgen-dependent signaling pathway networks. This ligand-dependent transcriptional factor modulates gene expression through the recruitment of various coregulator complexes, the induction of chromatin reorganization, and epigenetic histone modifications at target genomic loci. Dysregulation of androgen/AR signaling perturbs normal reproductive development and accounts for a wide range of pathological conditions such as androgen-insensitive syndrome, prostate cancer, and spinal bulbar muscular atrophy. In this review we summarize recent advances in understanding of the epigenetic mechanisms of AR action as well as newly recognized aspects of AR-mediated androgen signaling in both men and women. In addition, we offer a perspective on the use of animal genetic model systems aimed at eventually developing novel therapeutic AR ligands.

Noninvasive detection and prediction of bladder cancer by fluorescence in situ hybridization analysis of exfoliated urothelial cells in voided urine.

OBJECTIVES To investigate the clinical utility of fluorescence in situ hybridization (FISH) of voided urine in the detection of bladder cancer and the prediction of its recurrence. METHODS FISH with centromere-specific probes for chromosomes 9 and 17 was performed to evaluate the chromosomal alterations of exfoliated urothelial cells in voided urine obtained from 44 patients with bladder cancer and 20 controls. The analysis was also performed in 17 patients with bladder cancer after complete transurethral resection to prospectively determine whether FISH can predict tumor recurrence. RESULTS The sensitivity to detect bladder cancer by FISH analysis (85%) was significantly higher than that by urine cytologic examination (32%) and by the bladder tumor antigen test (64%) (P <0.0001 and P = 0.026, respectively). The specificity of FISH, cytologic analysis, and the bladder tumor antigen test was 95%, 100%, and 80%, respectively. Among the 17 patients tested after transurethral resection, 7 of 13 FISH-positive patients developed tumor recurrence within the 27-month follow-up period; none of 4 FISH-negative patients developed recurrence during the same period. The recurrence rate in patients with the loss of chromosome 17 was 100%, significantly higher than the 23% for patients without this alteration (P = 0.015). CONCLUSIONS These findings suggest that FISH analysis of exfoliated urothelial cells in voided urine can efficiently detect bladder cancer and predict its recurrence.

Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer

Prostate cancer development is associated with hyperactive androgen signaling. However, the molecular link between androgen receptor (AR) function and humoral factors remains elusive. A prostate cancer mouse model was generated by selectively mutating the AR threonine 877 into alanine in prostatic epithelial cells through Cre-ERT2–mediated targeted somatic mutagenesis. Such AR point mutant mice (ARpe-T877A/Y) developed hypertrophic prostates with responses to both an androgen antagonist and estrogen, although no prostatic tumor was seen. In prostate cancer model transgenic mice, the onset of prostatic tumorigenesis as well as tumor growth was significantly potentiated by introduction of the AR T877A mutation into the prostate. Genetic screening of mice identified Wnt-5a as an activator. Enhanced Wnt-5a expression was detected in the malignant prostate tumors of patients, whereas in benign prostatic hyperplasia such aberrant up-regulation was not obvious. These findings suggest that a noncanonical Wnt signal stimulates development of prostatic tumors with AR hyperfunction.

A Death Due to Perirenal Hematoma Complicating Extracorporeal Shockwave Lithotripsy

Abstract:  Perirenal hematoma is an occasional complication of extracorporeal shockwave lithotripsy (ESWL) which does not usually require treatment. A 79‐year‐old woman died 23 h after ESWL. Forensic autopsy was performed to determine whether medical treatment contributed to her death. The cause of death was hemorrhagic shock due to massive hematoma from a ruptured small vein in the perirenal adipose capsule. No injury to other organs was found and the patient had neither coagulation abnormality nor venous disease. Perirenal hematoma can easily be diagnosed with abdominal sonography, if pain or symptoms of anemia develop. Doctors must be aware of the possibilities of severe renal hematomas after ESWL.

MASSIVE ADRENOCORTICAL ADENOMA FOLLOWING LONG-TERM TREATMENT OF 21-HYDROXYLASE DEFICIENCY

Recent reports have revealed a high prevalence of small tumors in patients with untreated congenital adrenal hyperplasia due to 21-hydroxylase deficiency.1, 2 However, to our knowledge no case of long treated 21-hydroxylase deficiency complicated by a large adenoma has been reported in the literature. We report on a female patient with the simple virilizing form of 21-hydroxylase deficiency in whom a massive adrenal adenoma developed following 21 years of steroid treatment. CASE REPORT

Retraction: DNA demethylation in hormone-induced transcriptional derepression

This corrects the article DOI: 10.1038/nature08456

Intraurethral condylomata acuminata associated with genital piercings.

A 33-year-old man was referred to our institution with papillary masses at the urethral meatus and difficulty urinating. Genital examination showed two piercings on the frenulum, which were penetrating the external urethra. Endoscopic examination revealed papillary tumours over the entire circumference of the penile urethra and the piercing site. The tumours were resected transurethrally. Microscopic examination revealed condylomata acuminata. Human papillomavirus types 6 and 66 were detected in the lesions. Retrograde urethral viral infection is rare because of the protection provided by the mucosal immune system. Genital piercing may have facilitated spread of the human papillomavirus into the urethra.

DNA demethylation for hormone-induced transcriptional derepression

This corrects the article DOI: 10.1038/nature08456