p53 Antiproliferative Function Is Enhanced by Aspartate Substitution at Threonine 18 and Serine 20

Jabbur, James R.; Zhang, Wei

doi:10.4161/cbt.81

Cited by 23 publications

(23 citation statements)

References 49 publications

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“…Consistent with this, phosphomimetic amino acid substitutions at Ser 20 or Thr 18 can increase the specific activity of p53 as a transcription factor (28). As such, identification of the stressactivated Ser 20 kinases is an important goal in understanding the mechanisms underlying p53 activation as a tumor suppressor.…”

Section: (Ii) An Enhanced Green Fluorescent Protein (Egfp)-box-v Fumentioning

confidence: 75%

The MDM2 Ubiquitination Signal in the DNA-Binding Domain of p53 Forms a Docking Site for Calcium Calmodulin Kinase Superfamily Members

Craig

Chrystal

Fraser

et al. 2007

Molecular and Cellular Biology

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Section: (Ii) An Enhanced Green Fluorescent Protein (Egfp)-box-v Fumentioning

confidence: 75%

The MDM2 Ubiquitination Signal in the DNA-Binding Domain of p53 Forms a Docking Site for Calcium Calmodulin Kinase Superfamily Members

Craig

Chrystal

Fraser

et al. 2007

Molecular and Cellular Biology

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“…VRK1 appears to be expressed ubiquitously, at very different levels, in many tissues (34), and in murine embryos it is implicated in the early phases of hematopoietic development (49). VRK1 in vitro can phosphorylate human p53 in Thr18 (5,27), a residue that is essential for the interaction between p53 and Mdm2 (21,43). It also appears to have different expression patterns in specific tumor types (unpublished data).…”

Section: Vrk1-mediated P53 Stabilization Was Also Detected In Mdm2mentioning

confidence: 92%

p53 Stabilization and Accumulation Induced by Human Vaccinia-Related Kinase 1

Vega

Sevilla

Lazo

2004

Molecular and Cellular Biology

131

223

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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.Regulation of p53 levels plays a major role in determining the fate of a cell and its susceptibility to tumor development (17,19). The p53 protein is at a crossroad in the pathways implicated in the cellular response to many different types of stresses, such as genotoxic damage by UV or ionizing irradiation, hypoxia, and heat shock (36), and it has been implicated in different cell cycle checkpoints (7, 48). Several cell protection mechanisms are based on the ability of the p53 protein to regulate the progression of the cell cycle, the induction of apoptosis, or replicative senescence (6,46,50). These responses are controlled by the p53 protein level. p53 is a shortlived protein that is maintained at low levels in the cell under normal conditions and increases in response to stress. The levels and stability of the p53 protein in the cell are mainly controlled by its interactions with the negative regulator Mdm2 (hdm2 in humans) (3) or with other E3 ubiquitin ligases, such as COP1 (14) or Pirh2 (24). Mdm2 targets p53 for degradation by the ubiquitination pathway, promotes its nuclear export, and thus allows cell cycle progression (3). The new ubiquitin ligases COP1 and Pirh2 are also negative regulators of p53 function, targeting p53 for degradation by the proteasome in a ubiquitin-dependent fashion, and like Mdm2 are encoded by p53-inducible genes (14,24). Interactions with stabilizing proteins, such as p300 (53), MdmX ...

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“…Phosphorylation sites are frequently found in disordered regions of proteins that are poorly conserved (38). The detailed patterns of multisite phosphorylation in the p53 TAD have not been fully delineated, although it has been observed that simultaneous phosphorylation of Ser15 and Ser20, or Thr18 and Ser20, has synergistic effects on the p53 response (22)(23)(24). Multisite phosphorylation creates dynamic regulatory networks that respond precisely and quantitatively to cellular signals and have the potential for complex information processing (30,39).…”

Section: The Effects Of Multisite P53 Phosphorylation On Cbp Binding Arementioning

confidence: 99%

“…Simultaneous mutation of Ser18 and Ser23 to alanine leads to more severe defects in mice, suggesting that two-site or multisite phosphorylation has synergistic effects in activating the p53 response (22). When simultaneously phosphorylated, Thr18 and Ser20 in human p53 also appear to function synergistically to enhance the p53 response (23,24).…”

mentioning

confidence: 99%

Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation

Lee

Ferreon²,

Ferreon³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

199

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The transcriptional activity of p53 is regulated by a cascade of posttranslational modifications. Although acetylation of p53 by CREB-binding protein (CBP)/p300 is known to be indispensable for p53 activation, the role of phosphorylation, and in particular multisite phosphorylation, in activation of CBP/p300-dependent p53 transcriptional pathways remains unclear. We investigated the role of single site and multiple site phosphorylation of the p53 transactivation domain in mediating its interaction with CBP and with the ubiquitin ligase HDM2. Phosphorylation at Thr18 functions as an on/off switch to regulate binding to the N-terminal domain of HDM2. In contrast, binding to CBP is modulated by the extent of p53 phosphorylation; addition of successive phosphoryl groups enhances the affinity for the TAZ1, TAZ2, and KIX domains of CBP in an additive manner. Activation of p53-dependent transcriptional pathways requires that p53 compete with numerous cellular transcription factors for binding to limiting amounts of CBP/p300. Multisite phosphorylation represents a mechanism for a graded p53 response, with each successive phosphorylation event resulting in increasingly efficient recruitment of CBP/p300 to p53-regulated transcriptional programs, in the face of competition from cellular transcription factors. Multisite phosphorylation thus acts as a rheostat to enhance binding to CBP/p300 and provides a plausible mechanistic explanation for the gradually increasing p53 response observed following prolonged or severe genotoxic stress.competitive binding | protein-protein interaction | transcriptional coactivator | tumor suppressor

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p53 Antiproliferative Function Is Enhanced by Aspartate Substitution at Threonine 18 and Serine 20

Cited by 23 publications

References 49 publications

The MDM2 Ubiquitination Signal in the DNA-Binding Domain of p53 Forms a Docking Site for Calcium Calmodulin Kinase Superfamily Members

The MDM2 Ubiquitination Signal in the DNA-Binding Domain of p53 Forms a Docking Site for Calcium Calmodulin Kinase Superfamily Members

p53 Stabilization and Accumulation Induced by Human Vaccinia-Related Kinase 1

Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation

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