Mechanistic insights into steroid hormone-mediated regulation of the androgen receptor gene.

Expression of the androgen receptor is key to the response of cells and tissues to androgenic steroids, such as testosterone or dihydrotestosterone, as well as impacting the benefit of hormone-dependent therapies for endocrine diseases and hormone-dependent cancers. However, the mechanisms controlling androgen receptor expression are not fully understood, limiting our ability to effectively promote or inhibit androgenic signalling therapeutically. An autoregulatory loop has been described in which androgen receptor may repress its own expression in the presence of hormone, although the molecular mechanisms are not fully understood.

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain.

The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations.

Current and emerging approaches to noncompetitive AR inhibition.

The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration-resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand-binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance.

Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants.

The role of the androgen receptor (AR) in the progression of prostate cancer (PCa) is well established and competitive inhibition of AR ligand binding domain (LBD) has been the mainstay of antiandrogen therapies for advanced and metastatic disease. However, the efficacy of such drugs is often limited by the emergence of resistance, mediated through point mutations and receptor splice variants lacking the AR-LBD. As a result, the prognosis for patients with malignant, castrate-resistant disease remains poor.

Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators.

The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF.

Tissue control of androgen action: The ups and downs of androgen receptor expression.

The hormone testosterone plays crucial roles during male development and puberty and throughout life, as an anabolic regulator of muscle and bone structure and function. The actions of testosterone are mediated, primarily, through the androgen receptor, a member of the nuclear receptor superfamily. The androgen receptor gene is located on the X-chromosome and receptor levels are tightly controlled both at the level of transcription of the gene and post-translationally at the protein level.

Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia.

Schizophrenia is a debilitating familial neuropsychiatric disorder which affects 1% of people worldwide. Although the heritability for schizophrenia approaches 80% only a small proportion of the overall genetic risk has been accounted for, and to date only a limited number of genetic loci have been definitively implicated. We have identified recently through genetic and in vitro functional studies, a novel serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a rare risk factor for major mental disorders including schizophrenia.

An Sp1 Modulated Regulatory Region Unique to Higher Primates Regulates Human Androgen Receptor Promoter Activity in Prostate Cancer Cells.

Androgen receptor (AR) mediated signalling is necessary for normal development of the prostate gland and also drives prostate cancer (PCa) cell growth and survival, with many studies showing a correlation between increased receptor levels and therapy resistance with progression to fatal castrate recurrent PCa (CRPC). Although it has been held for some time that the transcription factor Sp1 is the main stimulator of AR gene transcription, comprehensive knowledge of the regulation of the AR gene remains incomplete. Here we describe and characterise in detail two novel active regulatory elements in the 5'UTR of the human AR gene.

Negative regulation of the androgen receptor gene through a primate-specific androgen response element present in the 5' UTR.

The androgen receptor (AR) is a widely expressed ligand-activated transcription factor which mediates androgen signalling by binding to androgen response elements (AREs) in normal tissue and prostate cancer (PCa). Within tumours, the amount of AR plays a crucial role in determining cell growth, resistance to therapy and progression to fatal castrate recurrent PCa in which prostate cells appear to become independent of androgenic steroids. Despite the pivotal role of the AR in male development and fertility and all stages of PCa development, the mechanisms governing AR expression remain poorly understood.

A phospholipase Cγ1-activated pathway regulates transcription in human vascular smooth muscle cells.

Aims: Growth factor-induced repression of smooth muscle (SM) cell marker genes is an integral part of vascular SM (VSM) cell proliferation. This is partly regulated via translocation of extracellular signal-regulated kinase 1/2 (ERK1/2) to the nucleus which activates the transcription factor Elk-1. The mediators involved in ERK1/2 nuclear translocation in VSM cells are unknown.

Sphingosylphosphorylcholine is a proinflammatory mediator in cerebral arteries.

Inflammation has an important function in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH); however, the mediators of this inflammatory response have not been clearly identified. In this study, we have investigated the potential function of two sphingolipids, which occur naturally in plasma and serum, sphingosylphosphorylcholine (SPC) and sphingosine 1-phosphate (S1P), to act as proinflammatory mediators in cerebral artery vascular smooth muscle (VSM) cells. In rat cerebral arteries, SPC but not S1P activated p38 mitogen-activated protein kinase (MAPK).

Amiloride-sensitive channels are a major contributor to mechanotransduction in mammalian muscle spindles.

We investigated whether channels of the epithelial sodium/amiloride-sensitive degenerin (ENaC/DEG) family are a major contributor to mechanosensory transduction in primary mechanosensory afferents, using adult rat muscle spindles as a model system. Stretch-evoked afferent discharge was reduced in a dose-dependent manner by amiloride and three analogues - benzamil, 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and hexamethyleneamiloride (HMA), reaching > or = 85% inhibition at 1 mm. Moreover, firing was slightly but significantly increased by ENaC delta subunit agonists (icilin and capsazepine).

The multi-functional role of sphingosylphosphorylcholine.

The sphingomyelin metabolite, sphingosylphosphorylcholine (SPC) has been the subject of much recent interest and controversy. Studies have indicated that SPC naturally occurs in plasma and a constituent of lipoproteins. Synthesis is also increased in some pathological conditions.

Spatial compartmentalization of tumor necrosis factor (TNF) receptor 1-dependent signaling pathways in human airway smooth muscle cells. Lipid rafts are essential for TNF-alpha-mediated activation of RhoA but dispensable for the activation of the NF-kappaB and MAPK pathways.

Tumor necrosis factor (TNF)-alpha-induced activation of RhoA, mediated by TNF receptor 1 (TNFR1), is a prerequisite step in a pathway that leads to increased 20-kDa light chain of myosin (MLC20) phosphorylation and airway smooth muscle contraction. In this study, we have investigated the proximal events in TNF-alpha-induced RhoA activation. TNFR1 is localized to both lipid raft and nonraft regions of the plasma membrane in primary human airway smooth muscle cells.

Tumor necrosis factor-alpha-induced activation of RhoA in airway smooth muscle cells: role in the Ca2+ sensitization of myosin light chain20 phosphorylation.

Tumor necrosis factor-alpha (TNF), an inflammatory cytokine, has a potentially important role in the pathogenesis of bronchial asthma and may contribute to airway hyper-responsiveness. Recent evidence has revealed that TNF can increase the Ca(2+) sensitivity of agonist-stimulated myosin light chain(20) (MLC(20)) phosphorylation and contractility in guinea pig airway smooth muscle (ASM). In the present study, the potential intracellular pathways responsible for this TNF-induced Ca(2+) sensitization were investigated.