The role of p53 in death of IL-3-dependent cells in response to cytotoxic drugs

Palacios, Carmen; Arroyo, Alicia G; Silva, A.; Collins, Mary

doi:10.1038/sj.onc.1203683

Cited by 16 publications

(12 citation statements)

References 32 publications

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“…Indeed Bax was not required for cell killing by a number of agents which inhibit nucleotide metabolism (hydroxyurea, methotrexate or FUdR) or which damage DNA (X-irradiation or cisplatin) (Table 1). This is in contrast to our ®ndings with p53-null IL-3 dependent cells which were highly resistant to the inhibitors of nucleotide metabolism, though not to DNA-damaging agents (Palacios et al, 2000). Therefore, although Bax can be up-regulated by p53 (Selvakumaran et al, 1995), Bax up-regulation cannot be required for p53-dependent cell killing by hydroxy-urea, methotrexate or FUdR.…”

Section: Role Of Bax In Apoptosis Of Il-3-dependent Cellscontrasting

confidence: 55%

Role of Bax in apoptosis of IL-3-dependent cells

et al. 2001

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Section: Role Of Bax In Apoptosis Of Il-3-dependent Cellscontrasting

confidence: 55%

Role of Bax in apoptosis of IL-3-dependent cells

et al. 2001

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“…Although the contribution of p53 to replication inhibitor-induced apoptosis appears to be cell-type dependent, our findings are congruent with earlier work showing that p53 expression is positively correlated with HU sensitivity. [6][7] Other studies have shown that p53 promotes apoptosis by trans-activating promoters of pro-apoptosis regulators including the BH3 domain containing proteins BAX, PUMA, and NOXA. 55 Whereas the levels of BAX were constitutively high in ML-1 cells, PUMA was induced following HU treatment, suggesting that this p53 target gene contributes to apoptosis induction ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…p53 expression was associated with apoptosis in IL-3-dependent bone marrow cells and EBV immortalized lymphoblasts, but other studies have failed to show a cause-and-effect link between p53 status and HU sensitivity. [6][7][8][9] Interestingly, an earlier report showed that HU induced a transcriptionally inert form of p53 in human RKO colon carcinoma cells, though this may have been a cell-type dependent phenomenon. [10][11] Stalled replication forks (RFs) arising secondary to dNTP depletion are a likely source of pro-apoptosis signals in HU-treated cells.…”

Section: Introductionmentioning

confidence: 99%

ATR Activation Necessary But Not Sufficient for p53 Induction and Apoptosis in Hydroxyurea-Hypersensitive Myeloid Leukemia Cells

Kumar

Dodson²,

Trinh³

et al. 2005

Cell Cycle

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Hydroxyurea (HU) is a competitive inhibitor of ribonucleotide reductase that is used for the treatment of myeloproliferative disorders. HU inhibits DNA replication and induces apoptosis in a cell type-dependent manner, yet the relevant pathways that mediate apoptosis in response to this agent are not well characterized. In this study, we employed the human myeloid leukemia 1 (ML-1) cell line as a model to investigate the mechanisms of HU-induced apoptosis. Exposure of ML-1 cells to HU caused rapid cell death that was accompanied by hallmark features of apoptosis, including membrane blebbing, phosphatidylserine translocation, and caspase activation. HU-induced apoptosis required new protein synthesis, was induced by HU exposures as short as 15 min, and correlated with the accumulation of p53 and induction of the p53 target gene PUMA. p53 induction in ML-1 cells was ATR dependent and downregulation of p53 through RNAi delayed HU-induced apoptosis. HU did not induce p53 or induce apoptosis in Molt-3 leukemia cells, even though exposure to HU induced a comparable level of DNA damage and robustly activated the ATR pathway. The microtubule inhibitor nocodazole suppressed HU-induced p53 accumulation in ML-1 cells suggesting that a microtubule-dependent event contributes to p53 induction and apoptosis in this cell line. Our findings outline an HU-induced cell death pathway and suggest that activation of ATR is necessary, but not sufficient, for stabilization of p53 in response to DNA replication stress.

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“…Whilst p53 is undoubtedly a central integrator of damage response pathways, not all genotoxic-mediated apoptosis is p53-dependent [107,108,[122][123][124][125][126][127][128]. In view of the recent identification of p63 and p73, proteins that have similarities to p53, p53-independent apoptosis after DNA damage might be mediated through activation of these p53 family members.…”

Section: The Role Of P53 Family Members In Damage Responsesmentioning

confidence: 99%

Cell and tissue responses to genotoxic stress

Coates

Lorimore

Wright

2005

The Journal of Pathology

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Cancers arise as a consequence of the accumulation of multiple genetic mutations in a susceptible cell, resulting in perturbation of regulatory networks that control proliferation, survival, and cellular function. Here, the sources of cellular stress that can cause oncogenic mutations and the responses of cells to DNA damage are reviewed. The role of different repair pathways and the potential for cell-and tissue-specific reliance on individual repair mechanisms are discussed. Evidence for cell-and tissue-specific activation of p53-mediated growth arrest and apoptosis after exposure to an individual genotoxin is assessed and some of the potential mediators of these different responses are provided. These cell-and tissuespecific responses to particular forms of DNA damage are likely to be key determinants of tissue-specific tumour susceptibility, and there is good evidence for genetic variations in these responses. The role that genotoxic agents play in altering the microenvironment to produce indirect effects on tumourigenesis through altered production of free radicals and cytokines that are characteristic of inflammatory-type processes is also evaluated. Changes to the microenvironment as direct or indirect effects of genotoxic stress can be involved in both tumour initiation and progression and may even be a prerequisite for tumourigenesis. Therefore, tumour susceptibility after endogenous or exogenous genotoxic stress represents a balance between cell-intrinsic responses of target cells and changes to the microenvironment. A fuller understanding of cell-and tissue-specific responses, alterations to the microenvironment, and genetic modifiers of these responses could lead to novel prevention and therapeutic strategies for common forms of human malignancy.

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The role of p53 in death of IL-3-dependent cells in response to cytotoxic drugs

Cited by 16 publications

References 32 publications

Role of Bax in apoptosis of IL-3-dependent cells

Role of Bax in apoptosis of IL-3-dependent cells

ATR Activation Necessary But Not Sufficient for p53 Induction and Apoptosis in Hydroxyurea-Hypersensitive Myeloid Leukemia Cells

Cell and tissue responses to genotoxic stress

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