2024-03-28T13:29:04Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/71242021-12-28T15:56:35Zcom_10261_112com_10261_1col_10261_365
p53 stabilization and accumulation induced by human vaccinia-related kinase 1
Vega, Francisco M.
Sevilla Hernández, Ana
Lazo, Pedro A.
VRK1
p53
Variations in intracellular levels of p53 regulate many cellular functions and determine tumor susceptibility.
Major mechanisms modulating p53 levels include phosphorylation and interaction of p53 with specific ubiquitin
ligases that promote its degradation. N-terminal phosphorylation regulates the interaction of p53 with
several regulatory molecules. Vaccinia-related kinase 1 (VRK1) is the prototype of a new Ser-Thr kinase family
in the human kinome. VRK1 is located in the nucleus outside the nucleolus. Overexpression of VRK1 increases
the stability of p53 by a posttranslational mechanism leading to its accumulation by a mechanism independent
of the Chk2 kinase. Catalytically inactive VRK1 protein (a K179E mutant) does not induce p53 accumulation.
VRK1 phosphorylates human p53 in Thr18 and disrupts p53-Mdm2 interaction in vitro, although a significant
decrease in p53 ubiquitination by Mdm2 in vivo was not detected. VRK1 kinase does not phosphorylate Mdm2.
VRK1-mediated p53 stabilization was also detected in Mdm2 / cells. VRK1 also has an additive effect with
MdmX or p300 to stabilize p53, and p300 coactivation and acetylation of p53 is enhanced by VRK1. The p53
stabilized by VRK1 is transcriptionally active. Suppression of VRK1 expression by specific small interfering
RNA provokes several defects in proliferation, situating the protein in the regulation of this process. VRK1
might function as a switch controlling the proteins that interact with p53 and thus modifying its stability and
activity. We propose VRK1 as the first step in a new pathway regulating p53 activity during cell proliferation.
F.M.V. and A. S. were supported by fellowships from Fundacio´n
Ramón Areces and the I3P program of the Consejo Superior de
Investigaciones Científicas. This work was funded by grants from the
Ministerio de Educación y Ciencia (SAF2000-0169 and SAF2004-
2900), the Fondo de Investigación Sanitaria (FIS-PI02-0585), the
Junta de Castilla y León (CSI18-03), the Fundación de Investigación
Médica MMA, and the Fundación Memoria Samuel Solórzano Barruso.
Peer reviewed
2008-09-05T16:52:02Z
2008-09-05T16:52:02Z
2004
artículo
http://purl.org/coar/resource_type/c_6501
Molecular and Cellular Biology 24(23): 10366-10389 (2004)
0270-7306
http://hdl.handle.net/10261/7124
10.1128/MCB.24.23.10366-10380.2004
15542844
en
http://dx.doi.org/10.1128/MCB.24.23.10366-10380.2004
open
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