RESUMO
The tumor suppressor von Hippel-Lindau, pVHL, is a multifaceted protein. One function is to dock to the hypoxia-inducible transcription factor (HIF) and recruit a larger protein complex that destabilizes HIF via ubiquitination, preventing angiogenesis and tumor development. pVHL also binds to the tumor suppressor p53 to activate specific p53 target genes. The oncogene Mdm2 impairs the formation of the p53-pVHL complex and activation of downstream genes by conjugating nedd8 to pVHL. While Mdm2 can impact p53 and pVHL, how pVHL may impact Mdm2 is unclear. Like p53 somatic mutations, point mutations are evident in pVHL that are common in renal clear cell carcinomas (RCC). In patients with RCC, Mdm2 levels are elevated, and we examined whether there was a relationship between Mdm2 and pVHL. TCGA and DepMap analysis revealed that mdm2 gene expression was elevated in RCC with vhl point mutations or copy number loss. In pVHL reconstituted or deleted isogenetically match RCC or MEF cell lines, Mdm2 was decreased in the presence of pVHL. Furthermore, through analysis using genetic and pharmacological approaches, we show that pVHL represses Mdm2 gene expression by blocking the MAPK-Ets signaling pathway and blocks Akt-mediated phosphorylation and stabilization of Mdm2. Mdm2 inhibition results in an increase in the p53-p21 pathway to impede cell growth. This finding shows how pVHL can indirectly impact the function of Mdm2 by regulating signaling pathways to restrict cell growth.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteínas Proto-Oncogênicas c-mdm2 , Transdução de Sinais , Proteína Supressora de Tumor p53 , Proteína Supressora de Tumor Von Hippel-Lindau , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Humanos , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão GênicaRESUMO
Oxyfluorides come in many different structures and are highly adaptable in composition, not least because of their mixed-anionic nature. Slight changes, unless specifically looked for, can easily go unnoticed. In this paper, we present two oxyfluorides, K3Mo2O5.6F3.4 and K3V2O3.3F5.7, synthesized under high-pressure/high-temperature conditions, and demonstrate the importance of careful analysis of composition, oxidation state and O/F anion distribution for an accurate description of oxyfluorides. Their crystal structures were determined by single-crystal X-ray diffraction and the transition metal cation valences analyzed by X-ray photoelectron spectroscopy (XPS). The O/F anion ratio was calculated using the principle of charge neutrality and the local distribution within the crystallographic framework was studied using bond valence (BV) and charge distribution (CHARDI) calculations. Madelung Part of Lattice Energy (MAPLE) calculations and magnetic measurements provide insight into phase stability and corroborate the mixed-valent nature of the compounds.
RESUMO
En este volumen se busca explorar las causas teóricas y empíricas que han hecho del método tipológico un recurso generalizado en el ámbito de los estudios agrarios, a la vez que se ensaya un bosquejo de presentación de problemas clásicos de la Sociología Rural centrando su atención en los paradigmas de análisis más difundidos e influyentes en América Latina
RESUMO
En este volumen se busca explorar las causas teóricas y empíricas que han hecho del método tipológico un recurso generalizado en el ámbito de los estudios agrarios, a la vez que se ensaya un bosquejo de presentación de problemas clásicos de la Sociología Rural centrando su atención en los paradigmas de análisis más difundidos e influyentes en América Latina