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ANALES?DE?LA?REAL?ACADEMIA?NACIONAL?DE?FARMACIA? Article

ISSN (Online) 1697-4298 analesranf.com

A historical overview of protein kinase PKR: from its discovery and
mechanism of action to its clinical and therapeutic implications

Title in Spanish: Una visión histórica de la proteína quinasa PKR: desde su descubrimiento y mecanismo de
acción hasta sus implicaciones clínicas y terapéuticas

María Ángel García Chaves 1

1Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos
III, 28029 Madrid, Spain.

ABSTRACT: The protein kinase R (PKR, also called RESUMEN: PKR, también llamada EIF2AK, es una
EIF2AK2) is an interferon-inducible double-stranded proteína quinasa de respuesta a ARN de doble cadena

RNA protein kinase with multiple effects on cells. PKR inducida por interferón que participa en múltiples
plays an active part in the cellular response to numerous efectos en las células. PKR contribuye de forma activa
types of stress, with a critical role in the host's en la respuesta celular a numerosos tipos de estrés,

interferon-induced antiviral defence mechanisms. PKR teniendo una importante función en el mecanismo de
has been extensively studied and documented for its defensa antiviral del hospedador inducido por los
relevance as a cell growth regulator, and more recently interferones. PKR ha sido estudiada intensamente a lo

analysed in connection with metabolism, inflammatory largo del tiempo documentando su relevancia también
processes, cancer, and neurodegenerative diseases. The como modulador del crecimiento celular, y más
present review will summarise, in chronological order, recientemente implicándola en metabolismo, procesos

the state of the knowledge about this kinase as well as inflamatorios, cáncer y enfermedades
the contributions we have done at the National Centre of neurodegenerativas. En esta revisión se resume de forma
Biotechnology regarding the regulation and mechanisms cronológica, el conocimiento adquirido sobre esta

of action of PKR. Specific mention will be made of the quinasa y nuestras contribuciones en el mecanismo de
studies that the author leads at the University Hospital acción y regulación de PKR llevadas a cabo en el Centro
Complex of Granada, showing the importance that PKR Nacional de Biotecnología. Además, con especial

has as a target of both conventional chemotherapeutics interés, se describen los estudios que la autora lidera en
and novel drugs, and its potential as a biomarker and el Complejo Hospitalario Universitario de Granada
therapeutic target in various pathologies. mostrando la importancia que PKR tiene como diana

molecular de quimioterapéuticos convencionales y
nuevos fármacos así como su potencial como
biomarcador y diana terapéutica en varias enfermedades.

*Corresponding Author: magciaves@yahoo.com An Real Acad Farm Vol. 82, Nº 2 (2016), pp. 143-167

Received: October 13, 2015 Accepted: June 27, 2016 Language of Manuscript: English

Premio Real Academia Nacional de Farmacia del Concurso Científico 2015 de la Real Academia Nacional de Farmacia

1. INTRODUCTION discovered after the important observations carried out by
the Metz and Kerr groups in the National Institute for
The Protein kinase R (PKR), also called eukaryotic Medical Research, London. In August 1972, an article by
translation initiation factor 2-alpha kinase 2 (EIF2AK2), is Dr Metz and Dr Esteban published in the Nature journal
an interferon-inducible double-stranded RNA protein showed how viral RNA could be detected in cells
kinase with multiple effects in cells (1, 2). PKR actively pretreated with interferon and infected with vaccinia virus,
contributes to the cellular response to numerous types of and how protein synthesis ceased early after infection.
stress, with a critical role in the antiviral defence They concluded that the effect of interferon must therefore
mechanism of the host induced by interferons. Interferon be at the stage of translation rather than transcription (6).
cytokines (IFNs) have a wide range of biological A few months later, Dr Kerr's group described the
functions, including antiviral, antiproliferative and inhibition of viral encephalomyocarditis messenger
immunomodulatory properties (3). The cloning of ribonucleic acid translation in L-cell extracts (7).
interferon genes, the structure of the ligand and their Subsequently, they showed the effect that the synthetic
receptors, and the signalling pathways and transcription of form of dsRNA (poly dIdC) had on translation (8). These
IFN-induced genes have been instrumental in reaching an seminal studies led to the identification in 1976 of a
understanding of how these molecules exert their function protein with dsRNA-dependent kinase activity involved in
in the cell (4, 5). Among the molecules with important translation modulation (9). The kinase activity responsible
biological function induced by IFN is PKR, which was
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@Real Academia Nacional de Farmacia. Spain