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A238L Inhibits NF-ATc2, NF-B, and c-Jun Activation through a Novel Mechanism Involving Protein Kinase C--Mediated Up-Regulation of the Amino-Terminal Transactivation Domain of p300¹

Aitor G. Granja^*, Neil D. Perkins and Yolanda Revilla^2,*

^* Centro de Biología Molecular "Severo Ochoa," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain; and School of Life Sciences, Division of Gene Regulation and Expression, University of Dundee, Dundee, Scotland, United Kingdom

The transcriptional coactivators CREB-binding protein and p300 regulate inducible transcription in multiple cellular processes and during the establishment of inflammatory and immune response. Several viruses have been shown to interfere with CREB-binding protein/p300 function, modulating their transcriptional activity. In this study, we report that the viral protein A238L interacts with the amino-terminal region of p300, inhibiting the acetylation and transcriptional activation of NF-ATc2, NF-B, and c-Jun in stimulated human T cells. We demonstrate that A238L modulates the autoacetylation of p300 without altering its intrinsic histone acetyl transferase activity. Furthermore, we show that the molecular mechanism of the inhibition executed by the viral protein is conducted through blocking protein kinase C (PKC)-p300 interaction and further acetylation in the amino-terminal transactivation domain of the coactivator, and that Ser³⁸⁴, within the CH1 domain, is essential for the full transcriptional activation of the coactivator. Moreover, we show that overexpression of an active form of PKC- reverts the A238L-mediated inhibition of the transcriptional activity of p300, showing, for the first time, a PKC--mediated up-regulation of the coactivator. These findings provide new strategies to develop therapies potentially useful in the control of disorders related to p300 deregulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Ministerio de Educación y Ciencia (BFU2004-00298/BMC) and by an institutional grant from the Fundación Ramón Areces. A.G.G. was funded by Centro de Investigación en Sanidad Animal.

² Address correspondence and reprint requests to Dr. Yolanda Revilla, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Madrid 28049, Spain. E-mail address: yrevilla{at}cbm.uam.es

³ Abbreviations used in this paper: CBP, CREB-binding protein; BCA, bicinchoninic acid; DAPI, 4',6'-diamidino-2-phenylindole; DBD, DNA-binding domain; HAT, histone acetyl transferase; Ion, calcium ionophore; MBP, myosin-binding protein; PKC, protein kinase C; RIPA, radioimmunoprecipitation assay; RLU, relative luminescence unit; TAD, transactivation domain; wt, wild type.

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