The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response.

Unlabelled: African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes.

Impact of soy lecithin, zinc oxide, and methylsulfonylmethane, as excipient ingredients, on the bioaccessibility and intestinal transport of branched-chain amino acids from animal and plant protein mixtures.

To maximize the biological activity of branched-chain amino acids (BCAAs), it is necessary to find a new excipient agent to increase the bioavailability of BCAAs in protein mixtures. The aim of the current study was to investigate the effects of soy lecithin (SLC), zinc oxide (ZnO), and methylsulfonylmethane (MSM) on the bioaccessibility and intestinal transport of BCAAs from animal and plant protein mixtures (PMs) an digestion model with human intestinal epithelial (Caco-2) cells. The bioaccessibility of total BCAAs in PMs considerably increased by 107.

Inhibition of GATA2 in prostate cancer by a clinically available small molecule.

Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription.

p38 MAPK Activity Is Required to Prevent Hyperactivation of NLRP3 Inflammasome.

Inflammation contributes to the pathogenesis and morbidity of wide spectrum of human diseases. The inflammatory response must be actively controlled to prevent bystander damage to tissues. Yet, the mechanisms controlling excessive inflammatory responses are poorly understood.

Post-Transcriptional Regulation of Alpha One Antitrypsin by a Proteasome Inhibitor.

Alpha one antitrypsin (α1AT), a serine proteinase inhibitor primarily produced by the liver, protects pulmonary tissue from neutrophil elastase digestion. Mutations of the gene results in a misfolded α1AT protein which aggregates inside hepatocytes causing cellular damage. Therefore, inhibition of mutant α1AT production is one practical strategy to alleviate liver damage.

Autophagy Is Required for Neutrophil-Mediated Inflammation.

Autophagy, an intracellular degradation and energy recycling mechanism, is emerging as an important regulator of immune responses. However, the role of autophagy in regulating neutrophil functions is not known. We investigated neutrophil biology using myeloid-specific autophagy-deficient mice and found that autophagy deficiency reduced neutrophil degranulation in vitro and in vivo.

Inflammasome activation by altered proteostasis.

The association between altered proteostasis and inflammatory disorders has been increasingly recognized, but the underlying mechanisms are not well understood. In this study, we show that deficiency of either autophagy or sequestosome 1 (p62 or SQSTM) led to inflammasome hyperactivation in response to LPS and ATP in primary macrophages and in mice in vivo. Importantly, induction of protein misfolding by puromycin, thapsigargin, or geldanamycin resulted in inflammasome activation that was more pronounced in autophagy- or p62-deficient macrophages.

MUDENG is cleaved by caspase-3 during TRAIL-induced cell death.

MUDENG, also known as AP5M1, was originally identified as an adaptin domain-containing gene that induced cell death in lymphoma cell lines. However, little is known of the mechanism responsible for MUDENG-mediated cell death. In this study, we investigated MUDENG changes during TRAIL-induced cell death.

DOBI is cleaved by caspases during TRAIL-induced apoptotic cell death.

Downstream of Bid (DOBI) known as Pus10, has been identified as a modulator of TRAIL-induced cell death using RNAi library screening. The crystal structure of DOBI has revealed that it is a crescent-shaped protein containing the pseudouridine synthase catalytic domain and a THUMP-containing domain. Here, we demonstrated that DOBI is expressed in various tissues such as heart and lung, and is also expressed in various tumor cells such as HeLa and A549.

TRAIL-induced cell death and caspase-8 activation are inhibited by cisplatin but not carboplatin.

Objective: Platinum (Pt) based drugs including cisplatin and carboplatin are widely used as anticancer drugs in various human cancers. Many studies have shown that chemotherapeutic agents synergistically enhance cell death induced by death ligands. However it has been recently reported that cisplatin may inhibit tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death through inactivation of caspases.

Homer1 regulates the susceptibility to TRAIL.

TRAIL is an apoptotic cell death-inducing ligand that belongs to a TNF superfamily. To identify the regulators that govern the susceptibility to TRAIL, TRAIL-resistant HeLa (TR) cells were established by repeatedly treating HeLa cells with TRAIL. Here we showed that scaffolding protein Homer1 plays a decisive role in regulating the apoptotic susceptibility to TRAIL.

A novel protein, MUDENG, induces cell death in cytotoxic T cells.

A screening system comprised of a randomized hybrid-ribozyme library has previously been used to identify pro-death genes in Fas-mediated apoptosis, and short sequence information of candidate genes from this system was previously reported by Kawasaki and Taira [H. Kawasaki, K. Taira, A functional gene discovery in the Fas-mediated pathway to apoptosis by analysis of transiently expressed randomized hybrid-ribozyme libraries, Nucleic Acids Res.

Generation of a novel proform of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein that can be reactivated by matrix metalloproteinases.

TRAIL has been suggested to induce the cell death in various tumor cells but not in normal cells; however, several studies have provided the evidence that TRAIL can induce the cell death in some normal cells including human normal hepatocytes, suggesting that TRAIL may show hepatic toxicity in human. In this study, we designed a pro-form of TRAIL (sTRAIL:IL-18) in that soluble TRAIL (sTRAIL) is fused to IL-18, and a matrix metalloproteinases (MMPs) cleavage site is introduced at the connecting site. We showed that sTRAIL:IL-18 has significantly diminished the killing activity in HeLa cells but regains the activity by releasing the free sTRAIL through MMP-2-mediated cleavage.

Cisplatin inactivation of caspases inhibits death ligand-induced cell death in vitro and fulminant liver damage in mice.

Cisplatin is a platinum-containing chemotherapeutic drug that has been widely used to treat various human cancers. It acts by forming inter- and intracross-links of DNA, which is believed to be a major cause for its therapeutic efficacy. However, little attention has been paid to the effect of cisplatin on death ligand-induced cell death.

Bid-cardiolipin interaction at mitochondrial contact site contributes to mitochondrial cristae reorganization and cytochrome C release.

Release of cytochrome c from the mitochondrial intermembrane space is critical to apoptosis induced by a variety of death stimuli. Bid is a BH3-only prodeath Bcl-2 family protein that can potently activate this efflux. In the current study, we investigated the mitochondrial localization of Bid and its interactions with mitochondrial phospholipids, focusing on their relationships with Bid-induced cytochrome c release.

The molecular mechanism of Noxa-induced mitochondrial dysfunction in p53-mediated cell death.

Genotoxic stresses stabilize the p53 tumor suppressor protein which, in turn, transactivates target genes to cause apoptosis. Although Noxa, a "BH3-only" member of the Bcl-2 family, was shown to be a target of p53-mediated transactivation and to function as a mediator of p53-dependent apoptosis through mitochondrial dysfunction, the molecular mechanism by which Noxa causes mitochondrial dysfunction is largely unknown. Here we show that two domains (BH3 domain and mitochondrial targeting domain) in Noxa are essential for the release of cytochrome c from mitochondria.

A novel zinc finger protein that inhibits osteoclastogenesis and the function of tumor necrosis factor receptor-associated factor 6.

A variety of surface receptors eliciting diverse cellular responses have been shown to recruit tumor necrosis factor receptor-associated factor (TRAF) adaptor molecules. However, a few TRAF-interacting intracellular proteins that serve as downstream targets or regulators of TRAF function have been identified. In search of new intracellular molecules that bind TRAF6, we carried out a yeast two-hybrid cDNA library screening with an N-terminal segment of TRAF6 as the bait.