Across species, animals have diverse sex determination pathways, each consisting of a hierarchical cascade of genes and its associated regulatory mechanism. Houseflies have a distinctive polymorphic sex determination system in which a dominant male determiner, the M-factor, can reside on any of the chromosomes. We identified a gene, (), as the M-factor. originated from a duplication of the spliceosomal factor gene (). Targeted disruption results in complete sex reversal to fertile females because of a shift from male to female expression of the downstream genes and The presence of on different chromosomes indicates that translocated to different genomic sites. Thus, an instructive signal in sex determination can arise by duplication and neofunctionalization of an essential splicing regulator.
Members of the cadherin family have been implicated as growth regulators in multiple tumor types. Based on recent studies from our laboratory implicating T-cadherin expression in mouse brain tumorigenesis, we examined the role of T-cadherin in astrocytoma growth regulation. In this report, we show that T-cadherin expression increased during primary astrocyte physiologic growth arrest in response to contact inhibition and serum starvation in vitro, suggesting a function for T-cadherin in astrocyte growth regulation. We further demonstrate that transient and stable reexpression of T-cadherin in deficient C6 glioma cell lines results in growth suppression. In addition, T-cadherin-expressing C6 cell lines demonstrated increased homophilic cell aggregation, increased cell attachment to fibronectin, and decreased cell motility. Cell cycle flow cytometry demonstrated that T-cadherin reexpression resulted in G 2 phase arrest, which was confirmed by mitotic index analysis. This growth arrest was p53 independent, as T-cadherin could still mediate growth suppression in p53 ؊/؊ mouse embryonic fibroblasts. T-cadherin-expressing C6 cell lines exhibited increased p21 CIP1/WAF1 , but not p27 Kip1 , expression. Lastly, T-cadherin-mediated growth arrest was dependent on p21 CIP1/WAF1 expression and was eliminated in p21 CIP1/WAF1 -deficient fibroblasts. Collectively, these observations suggest a novel mechanism of growth regulation for T-cadherin involving p21 CIP1/WAF1 expression and G 2 arrest.Astrocytomas are the most common primary malignant cancer affecting the nervous system, and despite aggressive therapy, the median survival of patients diagnosed with a highgrade astrocytoma (glioma) is only 9 to 12 months (35). These malignant glial tumors are hypothesized to develop as the result of the stepwise accumulation of specific genetic changes in astrocytes or astroglial precursors that promote astrocyte transformation and malignant progression (8). Genetic events important for astrocytoma formation and progression involve alterations in pathways involved in mitogenic signaling, cell cycle growth regulation, and environmental sensing. Previous studies have demonstrated that astrocytomas harbor changes in the epidermal and platelet-derived growth factor signaling pathways, involving amplification, mutation, or overexpression of these receptor tyrosine kinase molecules to result in increased mitogenic signaling. Similarly, astrocytomas harbor alterations in the p53 and retinoblastoma (Rb) cell cycle regulatory pathways. Inactivating mutations in the p53, p16, and Rb genes have been reported as well as overexpression of regulators of these pathways, including cyclin-dependent kinase 4 (cdk4) and MDM2.In contrast, alterations in molecules involved in environmental sensing have not been explored in great detail in astrocytomas. Gene expression profiling experiments from our laboratory on a mouse astrocytoma model have implicated the novel cadherin molecule, T-or H-cadherin, in astrocytoma progression. Based on these initial observ...
Six new lathyrane diterpenoids (1–6) and 10 known analogues (7–16), were separated from the seeds of Euphorbia lathyris. The absolute configuration of 1 was determined by X-ray crystallography, and the C-2′ configuration of 5 was elucidated by comparing experimental and calculated ECD data. These compounds were studied for their inhibition against nitric oxide (NO) generation induced by lipopolysaccharide in RAW264.7 macrophage cells. Compounds 1–3, 7, 9, 11, 13, 14, and 16 displayed inhibitory effects on NO production, with IC50 values of 2.6–26.0 μM. The new compound 1 (IC50 3.0 ± 1.1 μM), with no obvious cytotoxicity, was selected for further experiments. The production of cytokines such as IL-6 and IL-1β, as well as the protein expression of iNOS, NF-κB, and phosphorylated IκBα, was reduced by 1 dose-dependently. These results suggested that lathyrane diterpenoids may be used as potential anti-inflammatory agents and are worth being further researched.
Ganoderma lucidum, as food, tea, dietary supplement, and medicine, is widely used in China and Eastern Asian countries. In order to discover its anti-inflammatory constituents and provide some references for the usage of G. lucidum and G. sinense, two official species in China, the fruiting bodies of G. lucidum were studied, leading to the isolation of six new triterpenoids (1–6) and 27 known analogues (7–33). Compound 4 exhibited the most potent inhibition on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells. The production of IL-6 and IL-1β, as well as the expression of iNOS, COX-2, and NF-κB were dose-dependently reduced by 4. The phosphorylations of IκBα and IKKβ in LPS-induced macrophage cells were blocked by 4. Therefore, 4 could be used as a potential anti-inflammatory candidate and the total triterpenoids might be developed as value-added functional food for the prevention of inflammation. In combination of previous studies, it should be cautious for the interchangeable usage of G. lucidum and G. sinense.
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