A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function

Kokontis, John M.; Wagner, Andrew J.; O'Leary, Maura; Liao, Shutsung; Hay, Nissim

doi:10.1038/sj.onc.1204139

Cited by 72 publications

(55 citation statements)

References 39 publications

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“…We have been unable to test this directly since transcriptional inhibitors such as DRB and actinomycin D themselves affect p53 function and/or the state of phosphorylation of 4E-BP1 (Loreni et al, 2000;David-Pfeuty et al, 2001). Further studies, for example using mutant forms of p53 which are deficient in transcriptional transactivation or selectively defective in the ability to induce different sets of genes (Haupt et al, 1995;Ding et al, 2000;Kokontis et al, 2001), will therefore be required to establish the mechanism by which p53 controls translation as part of its function as a key factor in growth regulation and tumorigenesis. (Johnson et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation

et al. 2002

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p53 is an important regulator of cell cycle progression and apoptosis, and inactivation of p53 is associated with tumorigenesis. Although p53 exerts many of its effects through regulation of transcription, this protein is also found in association with ribosomes and several mRNAs have been identified that are translationally controlled in a p53-dependent manner. We have utilized murine erythroleukemic cells that express a temperature-sensitive p53 protein to determine whether p53 also functions at the level of translation. The data presented here demonstrate that p53 causes a rapid decrease in translation initiation. Analysis of several potential mechanisms for regulating protein synthesis shows that p53 has selective effects on the phosphorylation of the eIF4E-binding protein, 4E-BP1, and the activity of the p70 ribosomal protein S6 kinase. These data provide evidence that modulation of translational activity constitutes a further mechanism by which the growth inhibitory effects of p53 may be mediated.

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Section: Discussionmentioning

confidence: 99%

p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation

et al. 2002

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“…The c-myc oncogene can switch p53-dependent response to DNA damage from cell-cycle arrest to apoptosis by inhibiting p21 transactivation (Seoane et al, 2002). Similarly, p53 point mutants unable to transactivate p21 have been found to be more potent inducers of apoptosis than wild-type p53 (Bissonnette and Hunting, 1998;Kokontis et al, 2001). …”

Section: Introductionmentioning

confidence: 99%

p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation

2010

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p21 Waf1/Cip1 is a p53 transcription target implicated in both major functions of the tumor suppressor-cell cycle arrest and apoptosis. It is a potent inhibitor of the key cyclindependent kinases (CDK1-4), and has been thought to be the main mediator of p53-dependent G1 and G2 arrest. However, an increasing body of information suggests that in addition to its cell-cycle inhibitory activity, p21 can affect p53-dependent apoptosis. These data have been obtained from experiments in which p53 is activated primarily by genotoxic stress. In this study, we use the selective MDM2 antagonist, nutlin-3a, as a nongenotoxic p53 activator and show that the cell-cycle arrest function of p21 is dependent on the cellular context. In most cancer cell lines, p53-dependent p21 induction is essential for cellcycle arrest, but in some, p21 is dispensable. Depletion of p21 did not increase the apoptotic response to nutlin-3a in all seven cancer cell lines tested and p21 overexpression did not protect apoptosis-sensitive lines from death. p21 was found to mediate nutlin-induced p53-dependent downregulation of another antiapoptotic protein, survivin, without significantly affecting the apoptotic outcome. Taken together our results suggest that p21 induction does not affect the apoptotic response to nongenotoxic p53 activation.

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“…Many studies have indicated p53 being an important integral part of these checkpoints (Bargonetti and Manfredi, 2002). Accumulated p53 in response to DNA damage or through experimental overexpression has been shown to cause growth arrest at G1 (Agami and Bernards, 2000;Wesierska-Gadek and Schmid, 2000;Willers et al, 2000) and/or G2 (Agarwal et al, 1995;Taylor et al, 1999;Taylor and Stark, 2001;Nakamura et al, 2002) or to induce apoptosis (Vousden, 2000;Kokontis et al, 2001). In some cases, overexpression of the wt p53 induces cellular senescence (Sugrue et al, 1997;Dubrez et al, 2001;Jung et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Identification of PRC1 as the p53 target gene uncovers a novel function of p53 in the regulation of cytokinesis

Lin

2004

Oncogene

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Our previous studies conducted in MCF7-ptsp53 cells have demonstrated that overexpression of the wild-type (wt) p53 at permissive temperature 321C leads to growth arrest at the G2/M phase of the cell cycle. To identify novel p53-regulated genes that are responsible for the p53-induced G2/M arrest, we conducted cDNA microarray analyses. The array results indicated that the mRNA level of protein regulator of cytokinesis (PRC1) was significantly decreased when the p53 transactivation activity was turned on, suggesting that PRC1 transcription could be downregulated by p53. In this study, we have extensively examined the functional role of p53 in the regulation of PRC1, a cell cycle protein that plays important roles during cytokinesis. We demonstrate that increased expression of the wt p53 either by exogenous transfection or chemical induction results in reduced mRNA and protein expression of PRC1 in HCT116 p53 þ / þ , HCT116 p53 À/À , MCF-7, T47D, and HeLa cells. Importantly, we show that the decreased PRC1 expression is accompanied by the appearance of binucleated cells, indicating the process of cell division after mitosis being inhibited. By isolation and characterization of a 3 kb genomic fragment containing the 5 0 -flanking region and part of exon 1 of PRC1 gene, we demonstrate that p53 directly suppresses PRC1 gene transcription. We further locate the p53-responsive sequence to the proximal promoter region À214 to -163, relative to the transcriptional start site. The in vivo interaction of p53 with PRC1 gene promoter is further demonstrated by chromatin immunoprecipitation assay. Taken together, these new findings suggest that p53 may have important roles in the regulation of cytokinesis through controlling the transcription of PRC1.

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A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function

Cited by 72 publications

References 39 publications

p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation

p53 activation results in rapid dephosphorylation of the eIF4E-binding protein 4E-BP1, inhibition of ribosomal protein S6 kinase and inhibition of translation initiation

p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation

Identification of PRC1 as the p53 target gene uncovers a novel function of p53 in the regulation of cytokinesis

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