Early stages of p53-induced apoptosis are reversible

Geske, F. Jon; Lieberman, R.; Strange, Robert; Gerschenson, L. E.

doi:10.1038/sj.cdd.4400786

Cited by 139 publications

(107 citation statements)

References 42 publications

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“…Interestingly, a reversion of apoptosis occurs at the early stage of its onset because of the DNA repair (the middle row in Fig. 8A), which is consistent with the experimental observation (38). This happens when DNA damage is effectively repaired before the pro-apoptotic components are fully activated.…”

Section: An Overview Of Signal Transduction In the P53supporting

confidence: 76%

Cell fate decision mediated by p53 pulses

Zhang

Liu

Zhang

et al. 2009

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

219

208

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The tumor suppressor p53 plays a crucial role in cellular response to various stresses. Recent experiments have shown that p53 level exhibits a series of pulses after DNA damage caused by ionizing radiation (IR). However, how the p53 pulses govern cell survival and death remains unclear. Here, we develop an integrated model with four modules for the p53 network and explore the mechanism for cell fate decision based on the dynamics of the network. By numerical simulations, the following processes are characterized. First, DNA repair proteins bind to IR-induced double-strand breaks, forming complexes, which are then detected by ataxia telangiectasia mutated (ATM). Activated ATM initiates the p53 oscillator to produce pulses. Consequently, the target genes of p53 are selectively induced to control cell fate. We propose that p53 promotes the repair of minor DNA damage but suppresses the repair of severe damage. We demonstrate that cell fate is determined by the number of p53 pulses relying on the extent of DNA damage. At low damage levels, few p53 pulses evoke cell cycle arrest by inducing p21 and promote cell survival, whereas at high damage levels, sustained p53 pulses trigger apoptosis by inducing p53AIP1. We find that p53 can effectively maintain genomic integrity by regulating the efficiency and fidelity of DNA repair. We also show that stochasticity in the generation and repair of DNA damage leads to variability in cell fate. These findings are consistent with experimental observations and advance our understanding of the dynamics and functions of the p53 network.p53 network ͉ DNA repair ͉ apoptosis ͉ variability T he tumor suppressor protein p53 is a key mediator of cellular response to various stresses (1), and it performs its function primarily as a transcription factor, controlling the expression of a number of target genes (2). In response to DNA damage, the p53 signaling network is activated to induce cell cycle arrest, DNA repair, and apoptosis (1). Previously, it was proposed that p53 responds to DNA damage in an analog mode, i.e., a low level of p53 promotes cell survival by inducing cell cycle arrest and facilitating DNA repair, whereas a high level of p53 induces apoptosis to destroy irreparably damaged cells (1). Recently, damped oscillations of p53 level have been observed upon IR at the population level in several human cell lines and transgenic mice (3-6), with the amplitude of oscillations depending on the IR dose (5). More interestingly, pulses of p53 level were revealed in individual MCF7 cells, and the mean number of pulses, rather than the amplitude, was found to be related to the IR dose (7). This was suggested as a digital mode of p53 response (7). Later, it was further found that some MCF7 cells exhibit permanent p53 pulses whereas a few cells still show a finite number of p53 pulses during long-term observations (8). Such permanent oscillations may be related to the deficiency in DNA repair and apoptosis induction in those transformed cells (9-11). Moreover, the damped oscillations obse...

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Section: An Overview Of Signal Transduction In the P53supporting

confidence: 76%

Cell fate decision mediated by p53 pulses

Zhang

Liu

Zhang

et al. 2009

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

219

208

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“…However, even when the eventual outcome is cell death there is an initial period during which the effects of p53 are reversible, at least in transformed cells. 20,21 MEL cells do not become committed to apoptosis until at least 16 h after the activation of the tumour suppressor protein. 2 Moreover, in another system utilizing inducible p53, where protein synthesis is strongly impaired following induction, there is no obvious apoptosis for up to 4 days.…”

Section: Discussionmentioning

confidence: 99%

Regulation of translation factors eIF4GI and 4E-BP1 during recovery of protein synthesis from inhibition by p53

Constantinou

Clemens

2006

Cell Death Differ

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Activation of the tumour suppressor protein p53 rapidly inhibits protein synthesis. This is associated with dephosphorylation and cleavage of initiation factor eIF4GI and the eIF4E-binding protein 4E-BP1. When the activation of p53 is reversed within 16 h 4E-BP1 becomes rephosphorylated, the level of intact eIF4GI slowly increases and protein synthesis gradually recovers. The recovery of protein synthesis is partially blocked by rapamycin and wortmannin but not by the protein kinase inhibitors PD98059 and CGP74514A. Both rapamycin and wortmannin, but not PD98059 or CGP74514A, delay the reappearance of eIF4GI. In contrast, full-length 4E-BP1 rapidly becomes rephosphorylated and this process is partially inhibited by rapamycin, PD98059 and CGP74514A. Thus, activation of p53 results in the inhibition of distinct rapamycin-and wortmannin-sensitive pathways that target eIF4GI, and rapamycin-sensitive and -insensitive pathways that target 4E-BP1. Following inactivation of p53 the gradual recovery is determined largely by the kinetics of restoration of eIF4GI rather than by the rephosphorylation of full-length 4E-BP1. These findings suggest that the ability of cells to rephosphorylate 4E-BP1, resynthesise eIF4GI and restore the rate of protein synthesis after inactivation of p53 is an important aspect of recovery following the relief of physiological stress. Activation of the tumour suppressor protein p53 causes a rapid inhibition of protein synthesis which precedes the induction of a cell cycle block and subsequent apoptosis. 1-3The inhibition of translation is accompanied by early dephosphorylation and cleavage of the eukaryotic initiation factor (eIF)4E-binding protein 4E-BP1 as well as cleavage of polypeptide chain initiation factor eIF4GI and dephosphorylation of this protein at Ser 1108 . 3 The cleaved products of 4E-BP1 and eIF4GI, which are generated by a caspaseindependent mechanism, associate with eIF4E and there is a correspondingly decreased extent of interaction of eIF4E with full-length eIF4GI. These changes are likely to play an important role in impairing the initiation of protein synthesis.In this study, we have examined whether the inhibition of protein synthesis can be reversed when a temperaturesensitive form of p53 is inactivated, prior to the irreversible commitment to cell death, 2 by return of the cells to the non-permissive temperature (381C). We have also investigated the requirement for various signalling pathways that are known to regulate protein synthesis and have analysed the integrity and state of phosphorylation of eIF4GI and 4E-BP1 during the recovery phase. The results indicate a multifactorial mode of regulation of translation following the inactivation of p53 that is partially dependent on the activities of the protein kinase mammalian target of rapamycin (mTOR) and phosphatidylinositol-3-kinase (PI3k) but is independent of the protein kinases Mek1/2 and cdc2. Furthermore, our findings suggest that the rate of recovery of protein synthesis is limited by the kinetics of reappearance ...

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“…21 PS can also be expressed at low levels in a reversible fashion with cellular stress that does not necessarily commit a cell to death. [22][23][24][25][26][27][28][29][30] These relatively low levels of PS exposure can be readily reversed upon removal of physiologic stressors such as nitric-oxide, p53 activation, allergic mediators and growth factor deprivation.…”

mentioning

confidence: 99%

In vivo imaging of apoptosis

Blankenberg¹

2008

Cancer Biology & Therapy

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Early stages of p53-induced apoptosis are reversible

Cited by 139 publications

References 42 publications

Cell fate decision mediated by p53 pulses

Cell fate decision mediated by p53 pulses

Regulation of translation factors eIF4GI and 4E-BP1 during recovery of protein synthesis from inhibition by p53

In vivo imaging of apoptosis

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