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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Compared with pure water, the solubility of an ionic compound is less in aqueous solutions containing a common ion (one also produced by dissolution of the ionic compound). This is an example of a phenomenon known as the common ion effect, which is a consequence of the law of mass action that may be explained using Le Chȃtelier’s principle. Consider the dissolution of silver iodide:
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Transcription elongation is a dynamic process that alters depending upon the sequence heterogeneity of the DNA being transcribed. Hence, it is not surprising that the elongation complex's composition also varies along the way while transcribing a gene.
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Drug distribution in the human body is a complex process influenced by various individual factors, including age, pregnancy, obesity, diet, body water composition, pH levels, and specific disease conditions.
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Colligative Properties of Electrolytes
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Integración estructural en los factores inducibles por hipoxia

Dalei Wu1, Nalini Potluri1, Jingping Lu1

  • 1Metabolic Disease Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA.

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|August 7, 2015
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Resumen

Los factores inducibles a la hipoxia (HIF) regulan la adaptación celular a la falta de oxígeno, promoviendo el crecimiento tumoral. Las perspectivas estructurales en los heterodímeros HIF-α-ARNT revelan objetivos potenciales de fármacos contra el cáncer mediante el detalle de los sitios de unión de moléculas pequeñas.

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Área de la Ciencia:

  • La bioquímica
  • Biología molecular
  • Biología estructural

Sus antecedentes:

  • Los factores inducibles a la hipoxia (HIF) son reguladores críticos de las respuestas celulares al bajo nivel de oxígeno.
  • Los HIF controlan los genes involucrados en la eritropoiesis, la angiogénesis y el metabolismo, procesos vitales para el crecimiento y la progresión del tumor.
  • Los HIF son objetivos anticancerígenos atractivos debido a su papel en la tumorigénesis.

Objetivo del estudio:

  • Para aclarar la base estructural de la función heterodímero HIF-α-ARNT.
  • Identificar posibles sitios de unión de moléculas pequeñas en los heterodímeros HIF para la terapia dirigida contra el cáncer.
  • Comprender los mecanismos estructurales del reconocimiento del elemento de respuesta a la hipoxia (HRE).

Principales métodos:

  • Se utilizó la cristalografía de rayos X para determinar las estructuras de los heterodímeros HIF-2α-ARNT y HIF-1α-ARNT en ratones.
  • Las estructuras se resolvieron en complejo con moléculas pequeñas y ADN (elementos de respuesta de hipoxia).
  • Análisis de la arquitectura cuaternaria, bolsas de enlace de moléculas pequeñas e interfaces de enlace de ADN.

Principales resultados:

  • Se obtuvieron estructuras cristalinas detalladas de los heterodímeros HIF-2α-ARNT y HIF-1α-ARNT.
  • Se observó una arquitectura cuaternaria conservada, con ARNT en espiral alrededor de las subunidades HIF-α.
  • Se identificaron cinco bolsas de unión de moléculas pequeñas distintas, incluidos los sitios de dominio PAS y una cavidad interfacial.
  • La cabeza de unión al ADN y el dominio PAS distal cooperan para el reconocimiento eficiente del elemento de respuesta a la hipoxia.
  • Las mutaciones HIF-α asociadas con el cáncer se asignaron a regiones funcionalmente críticas que afectan la unión al ADN y la estabilidad del dominio.

Conclusiones:

  • Los datos estructurales proporcionan una comprensión mecanicista del montaje y la función de los heterodímeros HIF.
  • Los sitios de unión de moléculas pequeñas identificados ofrecen oportunidades para desarrollar nuevos fármacos contra el cáncer dirigidos a los HIF.
  • La comprensión de las interacciones HIF-ADN es crucial para el diseño de inhibidores que interrumpen los programas de transcripción oncogénicos.