Referencia

Genes &Dev(2012)26:1972-83

Autores

Roni H. G. Wright, Giancarlo Castellano, Jaume Bonet, Francois Le Dily, Jofre Font-Mateu, Cecilia Ballaré, A. Silvina Nacht, Daniel Soronellas1, Baldo Oliva and Miguel Beato(CRG, Barcelona)

Resumen

Eukaryotic gene regulation implies that transcription factors gain access to genomic information via poorly understood processes involving activation and targeting of kinases, histone-modifying enzymes, and chromatin remodelers to chromatin. Here we report that progestin gene regulation in breast cancer cells requires a rapid and transient increase in poly-(ADP)-ribose (PAR), accompanied by a dramatic decrease of cellular NAD that could have broad implications in cell physiology. This rapid increase in nuclear PARylation is mediated by activation of PAR polymerase PARP-1 as a result of phosphorylation by cyclin-dependent kinase CDK2. Hormone-dependent phosphorylation of PARP-1 by CDK2, within the catalytic domain, enhances its enzymatic capabilities. Activated PARP-1 contributes to the displacement of histone H1 and is essential for regulation of the majority of hormoneresponsive genes and for the effect of progestins on cell cycle progression. Both global chromatin immunoprecipitation (ChIP) coupled with deep sequencing (ChIP-seq) and gene expression analysis show a strong overlap between PARP-1 and CDK2. Thus, progestin gene regulation involves a novel signaling pathway that connects CDK2-dependent activation of PARP-1 with histone H1 displacement. Given the multiplicity of PARP targets, this new pathway could be used for the pharmacological management of breast cancer.

Descripción

Las hormonas esteroideas activan receptores específicos que son factores de transcripción activados pero también influencian numerosas vías de transmisión de señal por quinasas cuyos substratos finales son las histonas y otros factores que modifican la cromatina. En este papel mostramos que células de cáncer de mama tratadas con progesterona activan rápidamente la quinasa CDK2 que a su vez fosforila y activa PARP1 en el núcleo celular. La activación de PARP1 es necesaria para el desplazamiento de histona H1, la regulación génica y la proliferación celular en respuesta a hormona.

imagen noviembre

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo “Cromatina y Expresión Génica” que lidera Miguel Beato en el CRG se centra en los mecanismos moleculares de la regulación génica por hormonas esteroideas y en particular en la transmisión de señal hormonal por interacción con quinasas y en su impacto sobre la estructura y la dinámica de la cromatina. En los últimos años ha descifrado la importancia de la organización de las secuencias de respuesta a hormonas en nucleosomas y la complejidad del remodelado de cromatina en los primeros minutos de a las hormonas (revisión reciente:Beato &Vicent, Mol.Cell.Endocrinol.357:37-42, 2012).

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