HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers.

Incorporation of histone variant H3.3 comprises active territories of chromatin. Exploring the function of H3.

HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers.

Unlabelled: Incorporation of histone variant H3.3 comprises active territories of chromatin. Exploring the function of H3.

DAXX drives de novo lipogenesis and contributes to tumorigenesis.

Cancer cells exhibit elevated lipid synthesis. In breast and other cancer types, genes involved in lipid production are highly upregulated, but the mechanisms that control their expression remain poorly understood. Using integrated transcriptomic, lipidomic, and molecular studies, here we report that DAXX is a regulator of oncogenic lipogenesis.

Inhibition of Mps1 kinase enhances taxanes efficacy in castration resistant prostate cancer.

Androgen ablation therapy is the standard of care for newly diagnosed prostate cancer (PC) patients. PC that relapsed after hormonal therapy, referred to as castration-resistant PC (CRPC), often presents with metastasis (mCRPC) and is the major cause of disease lethality. The few available therapies for mCRPC include the Taxanes Docetaxel (DTX) and Cabazitaxel (CBZ).

βArrestin1 regulates glucocorticoid receptor mitogenic signaling in castration-resistant prostate cancer.

Background: Prostate cancer (PC) is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in males. The disease is initially treated with methods that inhibit androgen receptor (AR) signal transduction. Laboratory-based and clinical studies have identified alternative pathways that cause the failure of AR signal inhibition and consequent development of castration-resistant prostate cancer (CRPC).

Nuclear βArrestin1 regulates androgen receptor function in castration resistant prostate cancer.

Progression of prostate cancer (PC) to terminal castration-resistant PC (CRPC) involves a diverse set of intermediates, and androgen receptor (AR) is the key mediator of PC initiation and progression to CRPC. Hence, identification of factors involved in the regulation of AR expression and function is a necessary first-step to improve disease outcome. In this study, we identified ubiquitous βArrestin 1 (βArr1) as a regulator of AR function in CRPC.

Arginine vasopressin receptor 1a is a therapeutic target for castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) recurs after androgen deprivation therapy (ADT) and is incurable. Reactivation of androgen receptor (AR) signaling in the low androgen environment of ADT drives CRPC. This AR activity occurs through a variety of mechanisms, including up-regulation of AR coactivators such as VAV3 and expression of constitutively active AR variants such as the clinically relevant AR-V7.

Uropathogenic invades bladder epithelial cells by activating kinase networks in host cells.

Uropathogenic (UPEC) is the causative bacterium in most urinary tract infections (UTIs). UPEC cells adhere to and invade bladder epithelial cells (BECs) and cause uropathogenicity. Invading UPEC cells may encounter one of several fates, including degradation in the lysosome, expulsion to the extracellular milieu for clearance, or survival as an intracellular bacterial community and quiescent intracellular reservoir that can cause later infections.

Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival.

Background: Mutations or truncation of the ligand-binding domain (LBD) of androgen receptor (AR) underlie treatment resistance for prostate cancer (PCa). Thus, targeting the AR N-terminal domain (NTD) could overcome such resistance.

Methods: Luciferase reporter assays after transient transfection of various DNA constructs were used to assess effects of E1A proteins on AR-mediated transcription.

βArrestin2 Mediates Renal Cell Carcinoma Tumor Growth.

Renal Cell Carcinoma (RCC) is one of the most lethal urological cancers worldwide. The disease does not present early clinical symptoms and is commonly diagnosed at an advanced stage. Limited molecular drivers have been identified for RCC, resulting in the lack of effective treatment for patients with progressive disease.

Prostaglandin E2 receptor 4 mediates renal cell carcinoma intravasation and metastasis.

Treatment options for metastatic renal cell carcinoma (RCC) are limited. In this study, we investigated impact of prostaglandin E2 (PGE2) receptor 4 (EP4) on RCC metastasis. We found that knockdown of EP4 in two RCC cell lines, ACHN and SN12C, does not affect xenograft tumor take or growth rate in mice, but reduces metastasis by decreasing tumor intravasation.

Biased α-adrenergic receptor and βarrestin signaling in a cell culture model of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a common disease in older men that involves the enlargement of the prostate gland. This occurs in response to signal transduction initiated by α-adrenergic receptors (α-ARs). When bound to ligands, α-ARs stimulate the mitogenic extracellular signal-regulated kinases 1 and 2 (ERK) pathway, ultimately promoting stromal and epithelial cell hyperplasia in the prostate.

Feedback regulation of G protein-coupled receptor signaling by GRKs and arrestins.

GPCRs are ubiquitous in mammalian cells and present intricate mechanisms for cellular signaling and communication. Mechanistically, GPCR signaling was identified to occur vectorially through heterotrimeric G proteins that are negatively regulated by GRK and arrestin effectors. Emerging evidence highlights additional roles for GRK and Arrestin partners, and establishes the existence of interconnected feedback pathways that collectively define GPCR signaling.

The stress response neuropeptide CRF increases amyloid-β production by regulating γ-secretase activity.

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-β (Aβ) production. In cells, CRF treatment increases Aβ production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization.

Production of the Escherichia coli common pilus by uropathogenic E. coli is associated with adherence to HeLa and HTB-4 cells and invasion of mouse bladder urothelium.

Uropathogenic Escherichia coli (UPEC) strains cause urinary tract infections and employ type 1 and P pili in colonization of the bladder and kidney, respectively. Most intestinal and extra-intestinal E. coli strains produce a pilus called E.

G protein-coupled receptor kinase GRK5 phosphorylates moesin and regulates metastasis in prostate cancer.

G protein-coupled receptor kinases (GRK) regulate diverse cellular functions ranging from metabolism to growth and locomotion. Here, we report an important contributory role for GRK5 in human prostate cancer. Inhibition of GRK5 kinase activity attenuated the migration and invasion of prostate cancer cells and, concordantly, increased cell attachment and focal adhesion formation.

βArrestin1 regulates the guanine nucleotide exchange factor RasGRF2 expression and the small GTPase Rac-mediated formation of membrane protrusion and cell motility.

βArrestin proteins shuttle between the cytosol and nucleus and have been shown to regulate G protein-coupled receptor signaling, actin remodeling, and gene expression. Here, we tested the hypothesis that βarrestin1 regulates actin remodeling and cell migration through the small GTPase Rac. Depletion of βarrestin1 promotes Rac activation, leading to the formation of multipolar protrusions and increased cell circularity, and overexpression of a dominant negative form of Rac reverses these morphological changes.

Maintenance of androgen receptor inactivation by S-nitrosylation.

Antiandrogens target ligand-binding domain of androgen receptor (AR) and are used as first-line therapeutics to treat patients diagnosed with locally advanced and metastatic prostate cancer. Although initially beneficial as judged with actual tumor mass shrinkage, this therapy invariably fails and the cancer reappears as castration-resistant disease. Here, we report that increased intracellular nitric oxide (NO) levels lead to growth inhibition of both androgen-dependent and castration-resistant prostate tumors through a mechanism that involves AR function inactivation by S-nitrosylation of a single C601 residue present in the DNA-binding domain.

Protein s-nitrosylation measurement.

G protein-coupled receptors (GPCRs) are the most abundant and diverse type of cell surface receptors. GPCR signal duration and amplitude are both controlled by posttranslational modifications, principally phosphorylation. Emerging evidence demonstrates that the GCPRs and their effectors are also subject to S-nitrosylation modification.

Expansion of CCR8(+) inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas.

Purpose: Chemokines are involved in cancer-related inflammation and malignant progression. In this study, we evaluated expression of CCR8 and its natural cognate ligand CCL1 in patients with urothelial carcinomas of bladder and renal cell carcinomas.

Experimental Design: We examined CCR8 expression in peripheral blood and tumor tissues from patients with bladder and renal carcinomas.

Dynamin2 S-nitrosylation regulates adenovirus type 5 infection of epithelial cells.

Dynamin2 is a large GTPase that regulates vesicle trafficking, and the GTPase activity of dynamin2 is required for the multistep process of adenovirus infection. Activity of dynamin2 may be regulated by post-translational phosphorylation and S-nitrosylation modifications. In this study, we demonstrate a role for dynamin2 S-nitrosylation in adenovirus infection of epithelial cells.

Acute activation of β2-adrenergic receptor regulates focal adhesions through βArrestin2- and p115RhoGEF protein-mediated activation of RhoA.

β(2)-Adrenergic receptors (β(2)ARs) regulate cellular functions through G protein-transduced and βArrestin-transduced signals. β(2)ARs have been shown to regulate cancer cell migration, but the underlying mechanisms are not well understood. Here, we report that β(2)AR regulates formation of focal adhesions, whose dynamic remodeling is critical for directed cell migration.

Rap1GAP regulates renal cell carcinoma invasion.

Although patients with localized and regional kidney tumors have a high survival rate, incidence of mortality significantly increases for patients with metastatic disease. It is imperative to decipher the molecular mechanisms of kidney tumor migration and invasion in order to develop effective therapies for patients with advanced cancer. Rap1, a small GTPase protein, has been implicated in cancer cell growth and invasion.

G-protein coupled receptor kinase 5 regulates prostate tumor growth.

Purpose: The limited success of cancer therapeutics is largely attributable to the ability of cancer to become resistant to conventional cytotoxic chemotherapy. Thus, further identification of signaling molecules and pathways that influence tumorigenesis is needed to increase the overall therapeutic options. GRKs, originally recognized for their conserved role in GPCR signal control, have now emerged as regulators of additional biological molecules and functions.