Títol:
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CDK2-dependent activation of PARP-1 is required for hormonal gene regulation in breast cancer cells
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Autor/a:
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Wright, Roni H.G.; Castellano, Giancarlo; Bonet Martínez, Jaume, 1982-; Le Dily, François; Font Mateu, Jofre, 1977-; Ballaré, Cecilia Julia; Nacht, A. Silvina; Soronellas, Daniel; Oliva Miguel, Baldomero; Beato, Miguel
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Abstract:
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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 hormone-responsive 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. |
Abstract:
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The experimental work was supported by grants from the Departament d’Innovació Universitat i Empresa (DIUiE), Ministerio de Educación y Ciencia (MEC) BMC 2003-02902, Consolider (CSD2006-00049), Fondo de Investigación Sanitaria (FIS) PI0411605 and CP04/00087, FEDER BIO2008-0205, and EU IP HEROIC. |
Matèries:
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-Regulació genètica -Enzims -Mama -- Càncer -Mouse mammary tumor virus -Progesterone receptor -Transcriptional regulation -Histone H1 -PARP-1 -Chromatin remodeling |
Drets:
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© 2012 Genome Research by Cold Spring Harbor Laboratory Press. Published version available at http://genome.cshlp.org. |
Tipus de document:
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Article Article - Versió publicada |
Publicat per:
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Cold Spring Harbor Laboratory Press (CSHL Press)
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