SRRM4-mediated REST to REST4 dysregulation promotes tumor growth and neural adaptation in breast cancer leading to brain metastasis.

Background: Effective control of brain metastasis remains an urgent clinical need due a limited understanding of the mechanisms driving it. Although the gain of neuro-adaptive attributes in breast-to-brain metastases (BBMs) has been described, the mechanisms that govern this neural acclimation and the resulting brain metastasis competency are poorly understood. Herein, we define the role of neural-specific splicing factor Serine/Arginine Repetitive Matrix Protein 4 (SRRM4) in regulating microenvironmental adaptation and brain metastasis colonization in breast cancer cells.

A20 Restricts NOS2 Expression and Intestinal Tumorigenesis in a Mouse Model of Colitis-Associated Cancer.

Background And Aims: Colon cancer can occur sporadically or in the setting of chronic inflammation, such as in patients with inflammatory bowel disease. We previously showed that A20, a critical negative regulator of tumor necrosis factor signal transduction, could regulate sporadic colon cancer development. In this report, we investigate whether A20 also acts as a tumor suppressor in a model of colitis-associated cancer.

Neuronal exposure induces neurotransmitter signaling and synaptic mediators in tumors early in brain metastasis.

Background: Brain metastases (BM) are responsible for neurological decline and poor overall survival. Although the pro-metastatic roles of glial cells, and the acquisition of neuronal attributes in established BM tumors have been described, there are no studies that investigate the initial interplay between neurons and brain-seeking tumor cells. The aim of this study was to characterize early tumor-neuron interactions and the induced CNS-adaptive changes in tumor cells prior to macro-colonization.

A20 regulates canonical wnt-signaling through an interaction with RIPK4.

A20 is a ubiquitin-editing enzyme that is known to regulate inflammatory signaling and cell death. However, A20 mutations are also frequently found in multiple malignancies suggesting a potential role as a tumor suppressor as well. We recently described a novel role for A20 in regulating the wnt-beta-catenin signaling pathway and suppressing colonic tumor development in mice.

The distribution of BRAF gene fusions in solid tumors and response to targeted therapy.

Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 (0.

Effects of deletion of the transcription factor Nrf2 and benzo [a]pyrene treatment on ovarian follicles and ovarian surface epithelial cells in mice.

Polycyclic aromatic hydrocarbons, like benzo[a]pyrene (BaP), are ubiquitous environmental pollutants and potent ovarian toxicants. The transcription factor NRF2 is an important regulator of the cellular response to electrophilic toxicants like BaP and to oxidative stress. NRF2 regulates transcription of genes involved in the detoxification of reactive metabolites of BaP and reactive oxygen species.

Glutamate Cysteine Ligase Modifier Subunit (Gclm) Null Mice Have Increased Ovarian Oxidative Stress and Accelerated Age-Related Ovarian Failure.

Glutathione (GSH) is the one of the most abundant intracellular antioxidants. Mice lacking the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have decreased GSH. Our prior work showed that GSH plays antiapoptotic roles in ovarian follicles.

Glutathione-deficient mice have increased sensitivity to transplacental benzo[a]pyrene-induced premature ovarian failure and ovarian tumorigenesis.

Polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (BaP) are ubiquitous environmental pollutants found in tobacco smoke, air pollution, and grilled foods. Prenatal exposure to BaP causes premature reproductive senescence in mice, and other PAHs are transplacental ovarian carcinogens. Glutathione (GSH) is critical for detoxification of the reactive metabolites of PAHs.

Increased sensitivity to testicular toxicity of transplacental benzo[a]pyrene exposure in male glutamate cysteine ligase modifier subunit knockout (Gclm-/-) mice.

Polycyclic aromatic hydrocarbons (PAHs), like benzo[a]pyrene (BaP), are ubiquitous environmental pollutants formed by the incomplete combustion of organic materials. The tripeptide glutathione (GSH) is a major antioxidant and is important in detoxification of PAH metabolites. Mice null for the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have decreased GSH concentrations.

Lack of maternal glutamate cysteine ligase modifier subunit (Gclm) decreases oocyte glutathione concentrations and disrupts preimplantation development in mice.

Glutathione (GSH) is the most abundant intracellular thiol and an important regulator of cellular redox status. Mice that lack the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have decreased GSH synthesis. Nicotinamide nucleotide transhydrogenase, an inner mitochondrial membrane protein, catalyzes the interconversion of reduced nicotinamide adenine dinucleotide and reduced nicotinamide adenine dinucleotide phosphate; reduced nicotinamide adenine dinucleotide phosphate is required for reduction of GSH disulfide.

Knockout of the transcription factor NRF2 disrupts spermatogenesis in an age-dependent manner.

Oxidative stress occurs when generation of reactive oxygen species (ROS) overwhelms antioxidant defenses. Oxidative stress has been associated with male infertility. The transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) regulates basal and inducible transcription of genes encoding enzymes important for protection against ROS.

Follicle-stimulating hormone and estradiol interact to stimulate glutathione synthesis in rat ovarian follicles and granulosa cells.

Glutathione (GSH), the most abundant intracellular nonprotein thiol, is critical for many cellular functions. The rate-limiting step in GSH synthesis is catalyzed by glutamate cysteine ligase (GCL), a heterodimer composed of a catalytic (GCLC) and a modifier (GCLM) subunit. The tissue-specific regulation of GSH synthesis is poorly understood.

Induction of apoptosis by 9,10-dimethyl-1,2-benzanthracene in cultured preovulatory rat follicles is preceded by a rise in reactive oxygen species and is prevented by glutathione.

The polycyclic aromatic hydrocarbon (PAH) 9,10-dimethyl-1,2-benzanthracene (DMBA) destroys primordial, primary, and secondary ovarian follicles in rodents, but its effects on antral follicles have received limited attention. PAHs are metabolized to reactive species, some of which can undergo redox cycling to generate reactive oxygen species (ROS). We previously showed that ROS initiate apoptosis in preovulatory follicles cultured without gonadotropin support and that glutathione (GSH) depletion induces apoptosis in the presence of gonadotropins.