The spindle assembly checkpoint as a drug target - Novel small-molecule inhibitors of Aurora kinases

Cell division (mitosis) is a fundamental process in the life cycle of a cell. Equal distribution of chromosomes between the daughter cells is essential for the viability and well-being of an organism: loss of fidelity of cell division is a contributing factor in human cancer and also gives rise to miscarriages and genetic birth defects. For maintaining the proper chromosome number, a cell must carefully monitor cell division in order to detect and correct mistakes before they are translated into chromosomal imbalance. For this purpose an evolutionarily conserved mechanism termed the spindle assembly checkpoint (SAC) has evolved. The SAC comprises a complex network of proteins that relay and amplify mitosis-regulating signals created by assemblages called kinetochores (KTs). Importantly, minor defects in SAC signaling can cause loss or gain of individual chromosomes (aneuploidy) which promotes tumorigenesis while complete failure of SAC results in cell death. The latter event has raised interest in discovery of low molecular weight (LMW) compounds targeting the SAC that could be developed into new anti-cancer therapeutics. In this study, we performed a cell-based, phenotypic high-throughput screen (HTS) to identify novel LMW compounds that inhibit SAC function and result in loss of cancer cell viability. Altogether, we screened 65 000 compounds and identified eight that forced the cells prematurely out of mitosis. The flavonoids fisetin and eupatorin, as well as the synthetic compounds termed SACi2 and SACi4, were characterized in more detail utilizing versatile cell-based and biochemical assays. To identify the molecular targets of these SAC-suppressing compounds, we investigated the conditions in which SAC activity became abrogated. Eupatorin, SACi2 and SACi4 preferentially abolished the tensionsensitive arm of the SAC, whereas fisetin lowered also the SAC activity evoked by lack of attachments between microtubules (MTs) and KTs. Consistent with the abrogation of SAC in response to low tension, our data indicate that all four compounds inhibited the activity of Aurora B kinase. This essential mitotic protein is required for correction of erratic MT-KT attachments, normal SAC signaling and execution of cytokinesis. Furthermore, eupatorin, SACi2 and SACi4 also inhibited Aurora A kinase that controls the centrosome maturation and separation and formation of the mitotic spindle apparatus. In line with the established profound mitotic roles of Aurora kinases, these small compounds perturbed SAC function, caused spindle abnormalities, such as multi- and monopolarity and fragmentation of centrosomes, and resulted in polyploidy due to defects in cytokinesis. Moreover, the compounds dramatically reduced viability of cancer cells. Taken together, using a cell-based HTS we were able to identify new LMW compounds targeting the SAC. We demonstrated for the first time a novel function for flavonoids as cellular inhibitors of Aurora kinases. Collectively, our data support the concept that loss of mitotic fidelity due to a non-functional SAC can reduce the viability of cancer cells, a phenomenon that may possess therapeutic value and fuel development of new anti-cancer drugs.

Weekly Aurora, 21 February 1815 (vol. 5, no. 49) - Newspaper

Volumes of interest were published between 1812 and 1815 with articles about the War of 1812. Issue for Feb. 21, 1815, beginning on page 2 and continuing to take all of page 3 and some of page 4 is the full text headed: "TREATY OF PEACE" which is prefaced with an address by James Madison. Also in this issue is an article: "Victory At Orleans" and another article headed: "The War--From New Orleans".

Relación significativa entre tareas académicas y aplicaciones de lo aprendido [por] Perla Aurora Treviño Tamez

Tesis (Maestría en Enseñanza Superior) U.A.N.L.

Diseño y elaboración de un test de asertividad válido, confiable y tipificado [por] Aurora Moyano González

Tesis (Maestría en Psicología Laboral) U.A.N.L.

Análisis de los fundamentos constitucionales del federalismo fiscal mexicano [por] Aurora Gámez Cantú

Tesis ( Maestría en Derecho Fiscal ) U.A.N.L.

La Aurora, periódico político literario, Guadalajara 21 de marzo de 1830

UANL

Aurora poética de Jalisco : colección de poesías líricas de jóvenes jalisciences, dedicada al bello sexo de Guadalajara

UANL

[Ressenya del llibre Ullastret: guía de las excavaciones y su museo, d'Aurora Martín Ortega]

Ressenya del llibre Ullastret: guía de las excavaciones y su museo. Ullastret és un dels pocs jaciments que reuneixen les condicions òptimes per a ésser visitat. Però, per tal que sigui ben profitosa, calia oferir al visitant una guia que expliqués les principals característiques del lloc i el llibre de l’Aurora Martín ho fa

Orientalisme, colonialisme i gènere. ‘El Marroc sensual i fanàtic’ d'Aurora Bertrana

Els autors s’endinsen en aquest article en l’estudi de les relacions entre geografia, orientalisme i colonialisme a Europa al tombant del segle passat, tot introduint la perspectiva de gènere i en el marc d'un interès més general per la història del pensament geogràfic contemporani. Ho fan a partir de l’anàlisi contextualitzada d'un text de l’època que fa referència al cas espanyol i a la seva aventura colonial africana. Es tracta del llibre El Marroc sensual i fanàtic (1936) d’Aurora Bertrana, una versió molt elaborada del discurs de la diferència i una bona il•lustració de la literatura de viatges de dones europees, força excepcional i atípica -això sí- en el context literari català i espanyol de l’època

Projecte Comènius a l'IES Aurora Picornell : diversitat a l'escola europea. 'Proyecto Comenius en el IES Aurora Picornell : diversidad en la escuela europea'.

Resumen tomado de la publicación. Incluye tablas de datos e imágenes de las actividades

El programa d'intervenció educativa (PIE) de l'IES Aurora Picornell (2003-2004). 'El programa de intervenció educativa (PIE) del IES Aurora Picornell (2003-2004)'.

Este capítulo forma parte del apartado dedicado a la investigación e innovación pedagógica en las Islas Baleares. Estudio realizado por el Grupo de Investigación y de Formación Educativa y Social (GIFES) del Departamento de Ciencias de la Educación de la Universitat de les Illes Balears. Resumen tomado de la publicación, disponible en castellano y catalán

Aurora Díaz-Plaja : una bibliotecària destacada. 'Aurora Díaz-Plaja : una bibliotecaria destacada'.

Resumen en catalán del autor