Japanese nationwide observational multicenter study of tumor BRCA1/2 variant testing in advanced ovarian cancer.

The association between germline BRCA1 and BRCA2 pathogenic variants (mutations: gBRCAm) and ovarian cancer risk is well established. Germline testing alone cannot detect somatic BRCA1/2 pathogenic variants (sBRCAm), which is calculated based on the proportion of tumor BRCAm (tBRCAm) from tumor samples and gBRCAm. Homologous recombination deficiency (HRD) results mainly from genetic/epigenetic alterations in homologous recombination repair-related genes and can be evaluated by genomic instability status.

MGAT2 deficiency ameliorates high-fat diet-induced obesity and insulin resistance by inhibiting intestinal fat absorption in mice.

Background: Resynthesis of triglycerides in enterocytes of the small intestine plays a critical role in the absorption of dietary fat. Acyl-CoA:monoacylglycerol acyltransferase-2 (MGAT2) is highly expressed in the small intestine and catalyzes the synthesis of diacylglycerol from monoacylglycerol and acyl-CoA. To determine the physiological importance of MGAT2 in metabolic disorders and lipid metabolism in the small intestine, we constructed and analyzed Mgat2-deficient mice.

Nutrient control of phosphorylation and translocation of Foxo1 in C57BL/6 and db/db mice.

The nutrient response mediated by feeding or fasting plays an important role in controlling gluconeogenic gene expression such as glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxylase (PEPCK). The FOXO family of forkhead transcription factor Foxo1 (mouse FOXO1) is a key regulator that stimulates the expression of gluconeogenic genes in the nucleus but is phosphorylated by Akt (also known as protein kinase B; PKB) and translocated to the cytoplasm in response to insulin. Although it has been widely accepted that the cellular signaling of insulin represses Foxo1 function through Akt-dependent phosphorylation, the molecular mechanism behind the modulation of Foxo1 function by nutrient responses, including feeding or fasting, remains unknown in vivo.

Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation.

The FOXO family of forkhead transcription factors plays a key role in a variety of biological processes, including metabolism, cell proliferation, and oxidative stress response. We previously reported that Foxo1, a member of the FOXO family, is regulated through reversible acetylation catalyzed by histone acetyltransferase cAMP-response element-binding protein (CREB)-binding protein (CBP) and NAD-dependent histone deacetylase silent information regulator 2, and that the acetylation at Lys-242, Lys-245, and Lys-262 of Foxo1 attenuates its transcriptional activity. However, the molecular mechanism by which acetylation modulates Foxo1 activity remains unknown.

Identification of cis-regulatory sequences in the human angiotensinogen gene by transgene coplacement and site-specific recombination.

The function of putative regulatory sequences identified in cell transfection experiments can be elucidated only through in vivo experimentation. However, studies of gene regulation in transgenic mice (TgM) are often compromised by the position effects, in which independent transgene insertions differ in expression depending on their location in the genome. In order to overcome such a dilemma, a method called transgene coplacement has been developed in Drosophila melanogaster.

Mutation analysis of HNF-4 binding sites in the human glucose-6-phosphatase promoter.

HNF-4, a member of the nuclear receptor superfamily, binds to HNF-4 response elements (HRE), consisting of a direct repeat of the hexameric half-sites spaced by 1 nt (direct repeat 1) and activates a number of genes, which play central roles in fatty acids and glucose metabolism. Glucose-6-phosphatase (G6Pase) catalyzes the terminal step in the gluconeogenic and glycogenolytic pathways. A previous study has shown that HNF-4 binds to two DR1s in the regions A (located between -266 and -234) and B (located between -306 and -274) on the human G6Pase promoter.