Expression of Different Mutant p53 Transgenes in Neuroblastoma Cells Leads to Different Cellular Responses to Genotoxic Agents

Gangopadhyay, S B; Jalali, Farid; Reda, Danny; Peacock, Judith A.; Bristow, Robert G.; Benchimol, Samuel

doi:10.1006/excr.2002.5493

Cited by 18 publications

(18 citation statements)

References 33 publications

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“…In a recent study, 55 Chang and Lai demonstrated that some, but not all, TP53 mutations enhanced sensitivity of bladder cancer cells to cisplatin and doxorubicin. In a separate study, Gangopadhyay et al 56 showed opposing effects of W143A and R193P substituted p53 proteins on the sensitivity of neuroblastoma cells to cisplatin. These results may reflect differences in biochemical activities of the altered proteins, in terms of transactivational ability and spec- ificity for target promoters, as well as the ability to interact with other cellular proteins.…”

Section: Figure 4 -Effect Of H179l On Bax and P21mentioning

confidence: 95%

Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity

Wrighton

Prêle

Sunters

et al. 2004

Intl Journal of Cancer

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The p53 tumor suppressor protein is a critical mediator of cell cycle arrest and apoptosis in response to genotoxic stress. Abrogation of p53 function is a major feature of tumor development and may result in a compromised DNA-damage response. In our study, we examined the effect of expressing a human p53 cDNA, encoding a histidine to leucine amino acid substitution at codon 179 (H179L), on the ability of wild-type p53-containing NIH3T3 cells to respond to treatment with the chemotherapeutic cisplatin. After 72 hr of cisplatin treatment control cells underwent apoptosis preceded by a combination of S-and G 2 arrest, as judged by flow cytometry of propidium iodide-stained cells, and TUNEL and caspase-3 assays. This correlated with increased expression of the pro-apoptotic protein Bax. In contrast, cells stably expressing H179L-p53 arrested in S-phase following cisplatin treatment, which correlated with a marked decrease in the expression of cdc2, cyclin B1 and cyclin A, and a decrease in CDK2 and cyclin A-associated kinase activity. Interestingly, H179L p53 expressing cells underwent apoptosis earlier than control cells, indicating that this aberrant p53 may enhance cisplatin chemosensitivity. These data suggest that dominant-negative p53 can influence the expression and activity of CDK complexes, thereby modifying cell behavior following cisplatin-induced genotoxicity. © 2004 Wiley-Liss, Inc. Key words : cell cycle; cyclin; kinase; apoptosis; cisplatin Signaling pathways that control apoptosis and cell proliferation are highly conserved and strictly regulated in mammalian cells, and play critical roles during normal development and differentiation. These pathways are also important in the response to genotoxic agents, including many DNA-damaging chemotherapeutics currently used for cancer treatment. 1 The initial cellular response to DNA-damage includes cell cycle arrest, facilitating DNA repair, 2 thus preventing propagation of mutations to daughter cells. Tumor cells have a deregulated cell cycle and may respond to DNA-damage by triggering apoptosis. 3 Thus, the ability of cells to activate proapoptotic cascades is likely to be an important factor in determining treatment outcome for malignant disease.Cell cycle progression is driven by the activation of a series of serine/threonine protein kinases, known as cyclin dependent kinases (CDKs; for review, see reference 4). CDK activity is subject to tight regulation at several levels. First, these kinases must be phosphorylated by CDK-activating kinase, and dephosphorylated by cdc25 phosphatases, on specific residues. Second, association with the cognate cyclin, which is synthesized and degraded throughout the cell cycle, is required for activity. Third, CDK inhibitory proteins (CKIs) inhibit kinase activity at different stages of the cell cycle or, in some cases, may also act as assembly factors for CDK complexes. CKIs also play key roles under specific environmental conditions. For instance, in response to genotoxic damage, the p53 tumor suppressor protein...

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Section: Figure 4 -Effect Of H179l On Bax and P21mentioning

confidence: 95%

Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity

Wrighton

Prêle

Sunters

et al. 2004

Intl Journal of Cancer

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“…This stabilization leads to transcriptional activation of downstream effector genes (i.e. Bax, p21 WAF , Mdm2, Gadd45, 14-3-3s) resulting in cell cycle checkpoint activation, apoptosis, or terminal growth arrest dependent on tissue type, stressor, and level of damage (Lin and Benchimol, 1995;Wahl and Carr, 2001;Gangopadhyay et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…We have previously observed that relative resistance can be acquired in rat embryo fibroblasts (REF cells) and human neuroblastoma cells following transfection with a highly transforming, missense, core-DNA binding mutant p53 allele (i.e. MTp53pro193) that abrogates the G1 checkpoint (Slingerland et al, 1993;Bristow et al, 1998;Gangopadhyay et al, 2002). The acquired radioresistance was hypothesized to occur by transdominance of the MTp53pro193 protein, yet the possibility also remained that MTp53pro193 proteins have gain of function in mediating the resistant phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…This particular MTp53 allele was chosen as it had been associated with acquired radioresistance when it was expressed at high levels in all our previous studies utilizing rodent and human transfectants (Bristow et al, 1998;Gangopadhyay et al, 2002). The T63-R2 clone was chosen as it was relatively sensitive among the T63-ras clones and any increased radioresistance could be readily observed and tested (unlike the T63-R1 and T63-R3 clones, which were already highly resistant, presumably because of secondary genetic events).…”

Section: Introductionmentioning

confidence: 99%

“…For example, resistance to ionizing radiation in MTp53pro193-expressing cells may be mediated by increased DNA double-strand break rejoining or base excision repair. Similarly, repair of cis-platinum and UV irradiation would be mediated through altered nucleotide excision repair or DNA lesion bypass (Hoeijmakers, 2001;Gangopadhyay et al, 2002). Indeed, the expression of the MTp53pro193 protein consistently altered survival in the DNA repairassociated, low-dose shoulder region of the clonogenic survival curves in Figure 3, and the p53 protein has been implicated in a number of DNA repair pathways (Albor et al, 1998;Tang et al, 1999;Offer et al, 2001;Wiesmuller, 2001;Bernstein et al, 2002;Smith and Seo, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Resistance to DNA-damaging agents is discordant from experimental metastatic capacity in MEF ras-transformants-expressing gain of function MTp53

et al. 2003

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The attractive Achilles heel of germ cell tumours: an inherent sensitivity to apoptosis‐inducing stimuli

Spierings

Vries

Vellenga

et al. 2003

The Journal of Pathology

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Testicular germ cell tumours (TGCTs) are extremely sensitive to cisplatin-containing chemotherapy. The rapid time course of apoptosis induction after exposure to cisplatin suggests that TGCT cells are primed to undergo programmed cell death as an inherent property of the cell of origin. In fact, apoptosis induction of germ cells in the testis is an important physiological mechanism to control the quality and quantity of the gametes produced. Although p53 protein is highly expressed in the majority of TGCTs, almost no p53 mutations have been detected. Interestingly, p53 overexpression is associated with loss of p21 and gain of mdm2 expression, which might indicate a partial loss in functionality of the p53 regulatory pathway in TGCTs. Besides p21, TGCTs often show low expression of other proteins involved in the regulation of cell cycle progression, such as the retinoblastoma protein and members of the INK4 family. It can be postulated that the deregulated G(1)-S phase checkpoint results in premature entry into the S phase upon DNA damage. In addition to Bcl-2 family members that are involved in the regulation of germ cell apoptosis in the normal testis via the mitochondrial death pathway, the Fas death pathway is also known to regulate apoptosis of germ cells in the testis. Since chemotherapy has been shown to activate the Fas death pathway and TGCTs co-express both Fas and its ligand FasL, TGCT cells might undergo apoptosis upon cisplatin treatment via autocrine or paracrine activation of the Fas system by FasL. The hypothesis suggested here is that the lack of cell cycle arrest following a cisplatin-containing treatment, together with the activation of the Fas death pathway and the mitochondrial death pathway, explains the rapid and efficient apoptosis of TGCT cells. Defining the mechanisms involved in the cisplatin sensitivity of TGCTs will provide tools to increase cisplatin sensitivity in other human tumours with acquired or intrinsic resistance.

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Expression of Different Mutant p53 Transgenes in Neuroblastoma Cells Leads to Different Cellular Responses to Genotoxic Agents

Cited by 18 publications

References 33 publications

Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity

Aberrant p53 alters DNA damage checkpoints in response to cisplatin: Downregulation of CDK expression and activity

Resistance to DNA-damaging agents is discordant from experimental metastatic capacity in MEF ras-transformants-expressing gain of function MTp53

The attractive Achilles heel of germ cell tumours: an inherent sensitivity to apoptosis‐inducing stimuli

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