RESUMO
Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.
Assuntos
Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Japão , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
The involvement of the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD(+) salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD(+) salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition-induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment.
Assuntos
Autofagia , Citocinas/metabolismo , NAD/metabolismo , Neoplasias/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Proteína Tumoral p73/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Sobrevivência Celular , Citocinas/genética , Humanos , Células Jurkat , Células MCF-7 , NAD/genética , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Nicotinamida Fosforribosiltransferase/genética , Proteína Tumoral p73/genética , Proteína Supressora de Tumor p53/genéticaAssuntos
Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Proteínas Proto-Oncogênicas/genética , Receptores Notch/genética , Esquizofrenia/genética , Adulto , Idoso , Povo Asiático/genética , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Receptor Notch4RESUMO
15 micrograms bradykinin was given with large amount of physiological saline solution intravenously to dogs. Significantly greater diuresis and natriuresis were obtained compared with those of simple saline volume expansion experiments. Bradykinin in small doses which were selected as giving no influence on blood pressure enhanced additively diuresis and natriuresis, similarly with subpressor doses of A II, AVP, and MX in saline volume expanded dogs. Since all four agents are having cellular Ca-mobilizing action in common, it is suggested that phosphoinositide system may be involved in this enhancement of renal sodium and water excretion.
