The P53 pathway: what questions remain to be explored?

Levine, Arnold J.; Hu, Wenwei; Feng, Zhaohui

doi:10.1038/sj.cdd.4401910

Cited by 593 publications

(523 citation statements)

References 81 publications

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“…I n response to DNA damage, various protein kinases phosphorylate p53 at its amino terminus leading to the stabilization and accumulation of p53 protein 1,2 . As a guardian of the genome, p53 transactivates a number of its target genes to induce cell-cycle arrest or apoptosis and subsequently eliminates cells with risk of malignant transformation 3 .…”

mentioning

confidence: 99%

Regulation of histone modification and chromatin structure by the p53–PADI4 pathway

et al. 2012

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Histone proteins are modified in response to various external signals; however, their mechanisms are still not fully understood. Citrullination is a post-transcriptional modification that converts arginine in proteins into citrulline. Here we show in vivo and in vitro citrullination of the arginine 3 residue of histone H4 (cit-H4R3) in response to DnA damage through the p53-PADI4 pathway. We also show DnA damage-induced citrullination of Lamin C. Cit-H4R3 and citrullinated Lamin C localize around fragmented nuclei in apoptotic cells. Ectopic expression of PADI4 leads to chromatin decondensation and promotes DnA cleavage, whereas Padi4 − / − mice exhibit resistance to radiation-induced apoptosis in the thymus. Furthermore, the level of cit-H4R3 is negatively correlated with p53 protein expression and with tumour size in non-small cell lung cancer tissues. our findings reveal that cit-H4R3 may be an 'apoptotic histone code' to detect damaged cells and induce nuclear fragmentation, which has a crucial role in carcinogenesis.

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confidence: 99%

Regulation of histone modification and chromatin structure by the p53–PADI4 pathway

et al. 2012

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“…Activation of p53 affects the expression level of a large set of genes and mediates several cellular responses such as DNA repair, cell cycle arrest and/or apoptosis (Vogelstein et al, 2000;Levine et al, 2006). Although it is well established that p53 is a transcriptional regulator, transactivation-independent functions of p53 have been described (reviewed by He et al, 2007;Takwi and Li, 2009).…”

Section: Introductionmentioning

confidence: 99%

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

et al. 2011

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The mechanisms involved in the p53-dependent control of gene expression following DNA damage have not been completely elucidated. Here, we show that the p53 C terminus associates with factors that are required for the ultraviolet (UV)-induced inhibition of the mRNA 3 0 cleavage step of the polyadenylation reaction, such as the tumor suppressor BARD1 and the 3 0 processing factor cleavage-stimulation factor 1 (CstF1). We found that p53 can coexist in complexes with CstF and BARD1 in extracts of UV-treated cells, suggesting a role for p53 in mRNA 3 0 cleavage following DNA damage. Consistent with this, we found that p53 inhibits 3 0 cleavage in vitro and that there is a reverse correlation between the levels of p53 expression and the levels of mRNA 3 0 cleavage under different cellular conditions. Supporting these results, a tumor-associated mutation in p53 not only decreases the interaction with BARD1 and CstF, but also decreases the UV-induced inhibition of 3 0 processing, all of which is restored by wild-type-p53 expression. We also found that p53 expression levels affect the polyadenylation levels of housekeeping genes, but not of p21 and c-fos genes, which are involved in the DNA damage response (DDR). Here, we identify a novel 3 0 RNA processing inhibitory function of p53, adding a new level of complexity to the DDR by linking RNA processing to the p53 network.

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“…As a transcriptional target of p53, Mdm2 has control over its own expression (Barak et al, 1993;Wu et al, 1993). Mdm2 is upregulated in response to stimuli that activate p53, including g-irradiation, hyperproliferative signals and hypoxia (Levine et al, 2006). This feedback control of p53 by Mdm2 keeps p53 in check.…”

Section: Introductionmentioning

confidence: 99%

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

et al. 2007

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Mdm2, a regulator of the p53 tumor suppressor, is frequently overexpressed in lymphomas, including lymphomas that have inactivated p53. However, the biological consequences of Mdm2 overexpression in lymphocytes are not fully resolved. Here, we report that increased expression of Mdm2 in B cells augmented proliferation and reduced susceptibility to p53-dependent apoptosis, which was due to inhibition of p53 and suppression of p21 expression. Notably, developing and mature B cells from Mdm2 transgenic mice had an increased frequency of chromosomal/chromatid breaks and/or aneuploidy. This Mdm2-mediated genome instability occurred at a similar frequency as that in B cells overexpressing the oncogene c-Myc, but the chromosomal instability was not further enhanced when Mdm2 and c-Myc were overexpressed together. Elevated Mdm2 expression alone increased the occurrence of B-cell transformation in vivo and cooperated with c-Myc overexpression, resulting in an acceleration of B-cell lymphomagenesis. In addition, the frequency of p53 mutations was reduced, but not eliminated, in lymphomas arising in Mdm2/Emu-myc double transgenic mice. Therefore, increased Mdm2 expression facilitated B-cell lymphomagenesis, in part, through regulation of p53 by altering B-cell proliferation and susceptibility to apoptosis, and by inducing chromosomal instability

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The P53 pathway: what questions remain to be explored?

Cited by 593 publications

References 81 publications

Regulation of histone modification and chromatin structure by the p53–PADI4 pathway

Regulation of histone modification and chromatin structure by the p53–PADI4 pathway

p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

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