Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a mutant mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumors with OCCC-like histopathology, culminating in hemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting tumor cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signaling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumor growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodeling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signaling. We propose that ARID1A protects against inflammation-driven tumorigenesis.

Highlights d Multi-omics analysis and techniques with NASA's GeneLab platform d The largest cohort of astronaut data to date utilized for analysis d Mitochondrial dysregulation driving spaceflight health risks d NASA Twin Study data validates mitochondrial dysfunction during space missions

Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms.

The large Maf family of basic leucine-zipper-containing transcription factors are known regulators of key developmental and functional processes in various cell types, including pancreatic islets. Here, we demonstrate that within the adult pancreas, MafB is only expressed in islet ␣-cells and contributes to cell type-specific expression of the glucagon gene through activation of a conserved control element found between nucleotides ؊77 to ؊51. MafB was also shown to be expressed in developing ␣-and ␤-cells as well as in proliferating hormone-negative cells during pancreatogenesis. In addition, MafB expression is maintained in the insulin ؉ and glucagon ؉ cells remaining in mice lacking either the Pax4 or Pax6 developmental regulators, implicating a potentially early role for MafB in gene regulation during islet cell development. These results indicate that MafB is not only important to islet ␣-cell function but may also be involved in regulating genes required in both endocrine ␣-and ␤-cell differentiation. Diabetes 55:297-304, 2006 T he pancreatic islets of Langerhans are composed of ␣-, ␤-, ␦-, and pancreatic polypeptide cells, which independently produce the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively. Collectively, these hormones regulate both fuel and energy metabolism, with insulin and glucagon key to controlling glucose homeostasis (1). Thus, glucagon secreted from ␣-cells stimulates the mobilization of glucose through gluconeogenesis and glycogenolysis to prevent hypoglycemia, whereas ␤-cell-secreted insulin promotes glucose storage. Physiological glucose levels are maintained through the counter-regulatory actions of glucagon and insulin in peripheral tissues, with defects in ␣-and ␤-cell function playing a significant part in the ability of diabetic patients to maintain glycemic control.The identification and characterization of the transcription factors regulating insulin and glucagon expression have not only revealed their significance in islet function but also during pancreatogenesis. The pancreas develops from dorsal and ventral epithelial bud evaginations from the foregut, with glucagon-producing cells first appearing at mouse embryonic day (E) 9.5 in the dorsal bud (2-4). Insulin-producing cells emerge at E10.5 (3), whereas somatostatin and pancreatic polypeptide ϩ cells are not detected until E15.5 and E18.5, respectively (5). Insulin-and glucagon-producing cells appear in waves during development, with the functional ␣-and ␤-cells that will populate the islet produced starting at ϳE13.5 (5). This latter phase is termed the "secondary transition," and these cells continue to proliferate but are only organized into islet structures and become glucose-responsive shortly after birth (6).The transcription factors associated with controlling cell-specific expression of the insulin and glucagon genes are principal regulators of islet cell formation, including Pdx1 (7-10), Pax6 (11,12), Pax4 (13,14), and NeuroD1 (15,16). Pdx1 is necessary for the growth of the en...