The complexity of p53 stabilization and activation

Lavin, Martin F.; Gueven, Nuri

doi:10.1038/sj.cdd.4401925

Cited by 612 publications

(581 citation statements)

References 93 publications

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“…We identified two serine residues, serine 15 and serine 33, that are remarkably phosphorylated by rpS3 knockdown (Figure 2b). These data lead to the speculation that the p38-dependent phosphorylation is involved in the p53 induction, since it has been demonstrated previously that the phosphorylation at these sites is regulated mainly by p38 kinase (Bulavin et al, 1999;Lavin and Gueven, 2006), and has an effect on the stability and activity of p53 (Bulavin et al, 1999;Kishi et al, 2001).…”

Section: Rps3-knockdown Exhibits Aberrant Ribosome Biogenesismentioning

confidence: 88%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

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Section: Rps3-knockdown Exhibits Aberrant Ribosome Biogenesismentioning

confidence: 88%

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

2011

Oncogene

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“…Some of the modifications affect p53 localization and transcriptional activity, whereas certain modifications can direct p53 to a specific biological outcome, such as growth arrest versus apoptosis (reviewed by Meek, 2004;Lavin and Gueven, 2006). However, a fundamental requirement for p53 activation is the release of p53 from inhibition by the Mdm proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Most relevant to the relief from the Mdm proteins are the phosphorylation of Ser20, Thr18 and Ser15, which reside within the highly conserved hydrophobic loop that mediates p53 binding to the Mdm proteins. These phosphorylations protect p53 from inhibition by the Mdm proteins (Lavin and Gueven, 2006). Thr18 phosphorylation is considered the more critical of the two, as it directly attenuates its interaction with Mdm2 (Craig et al, 1999;Lai et al, 2000;Sakaguchi et al, 2000;Schon et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

PML enhances the regulation of p53 by CK1 in response to DNA damage

et al. 2008

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In response to stress, p53 is accumulated and activated to induce appropriate growth inhibitory responses. This requires the release of p53 from the constraints of its negative regulators Mdm2 and Mdm4. A key event in this dissociation is the phosphorylation of p53 at threonine residue (Thr18) within the Mdm2/4-binding domain. Casein kinase 1 (CK1) plays a major role in this phosphorylation. The promyelocytic leukemia protein (PML) regulates certain modifications of p53 in response to DNA damage. Here, we investigated the role of PML in the regulation of Thr18 phosphorylation. We found that PML enhances Thr18 phosphorylation of endogenous p53 in response to stress. On DNA damage, CK1 accumulates in the cell, with a proportion concentrated in the nucleus together with p53 and PML. Furthermore, CK1 interacts with endogenous p53 and PML, and this interaction is enhanced by genotoxic stress. Inhibition of CK1 impairs the protection of p53 by PML from Mdm2-mediated degradation. Our findings support a role for PML in the regulation of p53 by CK1. We propose that following DNA damage, PML facilitates Thr18 phosphorylation by recruiting p53 and CK1 into PML nuclear bodies, thereby protecting p53 from inhibition by Mdm2, leading to p53 activation.

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“…Among kinase-dependent activity pathways acting on p53, only two are controlled by Ca 2 þ signaling. One of them involves serine/threonine kinase members included in a subgroup of the protein kinase C (PKC) family termed the classical group encompassing PKCs-a, -bI, -bII and -g. [24][25][26] The other one is facilitated by the ubiquitous Ca 2 þ -sensing protein CaM and occurs through activation of members contained in the superfamily of CaM-dependent kinases. [27][28][29] As a selective inhibitor of PKC (PKC412) did not attenuate p53 S15 phosphorylation in any of the concentrations tested, we concluded that this kinase did not contribute to the 5-FUinduced and Ca 2 þ -dependent events leading to p53 activity.…”

Section: Dr5mentioning

confidence: 99%

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

et al. 2012

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5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2 þ ) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2 þ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2 þ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FUinduced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 À / À cells confirmed the importance of a Ca 2 þ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes.

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The complexity of p53 stabilization and activation

Cited by 612 publications

References 93 publications

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

PML enhances the regulation of p53 by CK1 in response to DNA damage

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

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