Cadmium Induces Conformational Modifications of Wild-type p53 and Suppresses p53 Response to DNA Damage in Cultured Cells

Wild-type p53 is involved in cellular response to DNA damage including cell cycle control, DNA repair and activation of apoptosis. Accumulation of p53 protein following DNA damage may initiate the apoptotic process, resulting in cell death. DNA damage induced by radiation is an example of apoptotic stimulus involving p53. Regulation of apoptosis by p53 can occur through transcriptional regulation of pro-apoptotic (e.g. bax) and anti-apoptotic (e.g. bel-2) factors. Although wild-type p53 usually sensitizes cells to radiation therapy, p53 mutations have a variable effect on radiation response. For example p53 mutations in bone or breast tumors have been found to be associated with resistance to chemotherapeutic drugs or ionizing radiation. Mutated p53 has has been reported to increase sensitivity to radiation and drugs in colorectal and bladder tumors. The present brief commentary tries to find an explanation at molecular level of these conflicting results.

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Enhanced DNA binding capacity on up‐regulated epidermal wild‐type p53 in vitiligo by H 2 O 2 ‐mediated oxidation: a possible repair mechanism for DNA damage

The FASEB Journal ◽

10.1096/fj.09-132621 ◽

2009 ◽

Vol 23 (11) ◽

pp. 3790-3807 ◽

Cited By ~ 50

Author(s):

Mohamed M. A. E. L. Salem ◽

Mohammad Shalbaf ◽

Nicholas C. J. Gibbons ◽

Bhaven Chavan ◽

J. M. Thornton ◽

...

Keyword(s):

Dna Damage ◽

Dna Binding ◽

Binding Capacity ◽

Wild Type ◽

Repair Mechanism ◽

Wild Type P53 ◽

Mediated Oxidation

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Down-regulation of Wild-type p53-induced Phosphatase 1 (Wip1) Plays a Critical Role in Regulating Several p53-dependent Functions in Premature Senescent Tumor Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m112.435149 ◽

2013 ◽

Vol 288 (23) ◽

pp. 16212-16224 ◽

Cited By ~ 16

Author(s):

Elvira Crescenzi ◽

Zelinda Raia ◽

Francesco Pacifico ◽

Stefano Mellone ◽

Fortunato Moscato ◽

...

Keyword(s):

Dna Damage ◽

Tumor Cells ◽

Dna Damage Response ◽

Critical Role ◽

Wild Type ◽

Down Regulation ◽

Senescent Phenotype ◽

Response To Chemotherapy ◽

Damage Response ◽

Wild Type P53

Premature or drug-induced senescence is a major cellular response to chemotherapy in solid tumors. The senescent phenotype develops slowly and is associated with chronic DNA damage response. We found that expression of wild-type p53-induced phosphatase 1 (Wip1) is markedly down-regulated during persistent DNA damage and after drug release during the acquisition of the senescent phenotype in carcinoma cells. We demonstrate that down-regulation of Wip1 is required for maintenance of permanent G2 arrest. In fact, we show that forced expression of Wip1 in premature senescent tumor cells induces inappropriate re-initiation of mitosis, uncontrolled polyploid progression, and cell death by mitotic failure. Most of the effects of Wip1 may be attributed to its ability to dephosphorylate p53 at Ser15 and to inhibit DNA damage response. However, we also uncover a regulatory pathway whereby suppression of p53 Ser15 phosphorylation is associated with enhanced phosphorylation at Ser46, increased p53 protein levels, and induction of Noxa expression. On the whole, our data indicate that down-regulation of Wip1 expression during premature senescence plays a pivotal role in regulating several p53-dependent aspects of the senescent phenotype.

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Bcl-2 Protects against p53-Induced Apoptosis through Hdm2

Blood ◽

10.1182/blood.v112.11.5333.5333 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5333-5333

Author(s):

Line Wergeland ◽

Kevin B. Spurgers ◽

Eystein Oveland ◽

Torill Høiby ◽

Manel Cascallo ◽

...

Keyword(s):

Dna Damage ◽

Acute Myeloid Leukemia ◽

Protein Level ◽

Myeloid Leukemia ◽

Proteasome Inhibitors ◽

Wild Type ◽

Inhibitory Molecule ◽

Wild Type P53 ◽

Induced Apoptosis ◽

Acute Myeloid

Abstract Hdm2 is up-regulated in several malignancies including sarcomas and acute myeloid leukemia, where it counteracts the anti-proliferative and pro-apoptotic effect of wild type p53. The anti-apoptotic protein Bcl-2 is often elevated in many tumors with wild type p53 and serves to block p53-induced apoptosis. We demonstrate that the protein level of Hdm2 positively correlates with the level of Bcl-2 and follows the Bcl-2 level in different cell systems. Over-expression of Bcl-2 protects Hdm2 from DNA-damage induced degradation in a dose dependant manner. In addition, modulation of Bcl-2 by shRNA knockdown reduced the Hdm2 protein level in parallel. Consequently, treatment of AML cells with the Bcl-2 small inhibitory molecule HA14-1 attenuated the level of Hdm2. The Bcl-2 level, but not the DNA damage induced Hdm2 degradation, was affected by disruption of the E3 ubiquitin ligase activity of Hdm2. In addition, the DNA-damage induced Hdm2 down-regulation was blocked by disrupted E1 ubiquitin-activation, defect polyubiquitination and by proteasome inhibitors. Finally, we show that Bcl-2 protection from p53-induced cell death requires co-expression of Hdm2 in double null p53/mdm2 mouse embryonic fibroblasts. Our results indicate that Bcl-2 regulates the Hdm2 level and that Hdm2 is a key mediator in Bcl-2 inhibition of p53-induced apoptosis. This is of particular therapeutic interest for cancers displaying elevated Hdm2 and Bcl-2, like sarcoma and acute myeloid leukemia.

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Prevention of Fluorodeoxyuridine-Induced Cytotoxicity and DNA Damage in HT29 Colon Carcinoma Cells by Conditional Expression of Wild-Type p53 Phenotype

Molecular Pharmacology ◽

10.1124/mol.52.4.600 ◽

1997 ◽

Vol 52 (4) ◽

pp. 600-605 ◽

Cited By ~ 7

Author(s):

Leslie A. Parsels ◽

Richard C. Zellars ◽

Tania L. Loney ◽

Joshua D. Parsels ◽

Michael F. Clarke ◽

...

Keyword(s):

Dna Damage ◽

Colon Carcinoma ◽

Carcinoma Cells ◽

Wild Type ◽

Colon Carcinoma Cells ◽

Conditional Expression ◽

Wild Type P53

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Molecular analysis of different allelic variants of wild-type human p53

Biochemistry and Cell Biology ◽

10.1139/o92-145 ◽

1992 ◽

Vol 70 (10-11) ◽

pp. 1014-1019 ◽

Cited By ~ 8

Author(s):

France Moreau ◽

Greg Matlashewski

Keyword(s):

Cultured Cells ◽

Human Cancer ◽

P53 Protein ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Tumour Suppressor ◽

Allelic Variant ◽

Wild Type ◽

Allelic Variants ◽

Wild Type P53

The p53 tumour suppressor gene is intensively studied because mutations in this gene are the most common genetic alteration so far identified in human cancer. Considerable emphasis has thus been placed on characterizing the biological differences between mutant and wild-type p53 protein. This has led to the realization that in cultured cells, mutant p53 behaves like an oncogene, whereas wild-type p53 is a tumour suppressor gene. The p53 protein is also a target for the tumour virus oncogene products SV40 large T, adenovirus E1B, and human papillomavirus type 16 E6, which are all capable of forming complexes to the p53 protein. Although p53 represents an extremely important cellular regulatory molecule which is well conserved, there exists two allelic variants of wild-type human p53 that differ both in primary and confirmational structure. One variant contains an arginine at amino acid 72 (p53Arg), whereas the other form contains a proline at this residue (p53Pro). The possible implications for more than one allelic variant of wild-type human p53 in the general population is unknown. The present study was undertaken to compare some of the biological features of the different wild-type p53 variants. We present data demonstrating that there was a post-transcriptional selection against accumulation of both variants of wild-type human p53 in 3T3-A31 cells, arguing that both forms are proliferation inhibitory in these cells. Both variants of human p53 were stabilized by SV40 large T, but did not displace mouse p53 from SV40 large T. Neither allelic variant of human p53 was able to reduce significantly SV40-mediated anchorage-independent growth of 3T3-A31 cells. Taken together, these data suggest that although there are structurally different variants of wild-type human p53, there is no difference in the biological activity of these molecules at the level of the biological assays performed here.Key words: human p53, large T, transformation, oncogenes, tumour suppressor.

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Role ofp16INK4Ain Replicative Senescence and DNA Damage-Induced Premature Senescence in p53-Deficient Human Cells

Biochemistry Research International ◽

10.1155/2012/951574 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 28

Author(s):

Razmik Mirzayans ◽

Bonnie Andrais ◽

Gavin Hansen ◽

David Murray

Keyword(s):

Dna Damage ◽

Ionizing Radiation ◽

Replicative Senescence ◽

Human Cancer ◽

Human Cells ◽

Premature Senescence ◽

Wild Type ◽

Regulatory Relationship ◽

Human Cancer Cell Lines ◽

Wild Type P53

Thep16INK4A(hereafter p16) tumor suppressor is encoded by theINK4A/ARFlocus which is among the most commonly dysregulated sequences in human cancer. By inhibiting cyclin-dependent kinases, p16 activates the G1-S checkpoint, and this response is often considered to be critical for establishing a senescence-like growth arrest. Not all studies support a universal role for p16 in senescence. Single-cell analysis of noncancerous human fibroblast cultures undergoing senescence as a function of culture age (replicative senescence) has revealed that p16 is not expressed in the majority (>90%) of cells that exhibit features of senescence (e.g., flattened and enlarged morphology coupled with senescence-associatedβ-galactosidase expression), ruling out a requirement for p16 in this process. In addition, ionizing radiation triggers premature senescence in human cancer cell lines that do not express p16. These observations are made with cells that express wild-type p53, a key mediator of the DNA damage response. In this paper, we examine the growing evidence suggesting a negative regulatory relationship between p16 and p53 and discuss recent reports that implicate a role for p16 in replicative senescence and ionizing radiation-induced premature senescence in human cells that lack wild-type p53 function.

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The Chimeric E2A-HLF Transcription Factor Abrogates p53-Induced Apoptosis in Myeloid Leukemia Cells

Blood ◽

10.1182/blood.v92.4.1397.416k19_1397_1405 ◽

1998 ◽

Vol 92 (4) ◽

pp. 1397-1405

Author(s):

Rachel A. Altura ◽

Takeshi Inukai ◽

Richard A. Ashmun ◽

Gerard P. Zambetti ◽

Martine F. Roussel ◽

...

Keyword(s):

Dna Damage ◽

Cell Death ◽

B Cells ◽

Growth Factor ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Leukemia Cells ◽

Wild Type ◽

Wild Type P53 ◽

Induced Apoptosis

Leukemic lymphoblasts expressing the E2A-HLF oncoprotein possess wild-type p53 genes, but do not undergo apoptosis in response to DNA damage. Experimentally, E2A-HLF prevents apoptosis due to growth factor deprivation or γ-irradiation in interleukin-3 (IL-3)–dependent murine pro-B cells. To directly test the chimeric protein’s ability to abrogate p53-mediated cell death, we used mouse myeloid leukemia cells (M1p53tsval) that constitutively express a temperature-sensitive (ts) mutant p53 gene and undergo apoptosis when p53 assumes an active wild-type configuration. This effect is blocked by treatment with IL-6, which allows the cells to survive in culture despite wild-type p53 activation. We introduced E2A-HLF into M1p53tsval cells and found that they were resistant to p53-mediated apoptosis and that E2A-HLF effectively substituted for the survival functions of IL-6. The expression of p53-responsive genes such as p21 and Bax was upregulated normally, suggesting that E2A-HLF acts downstream of p53 to block execution of the p53-induced apoptotic program. NFIL3, a growth factor-regulated bZIP protein that binds to the same DNA-consensus site as E2A-HLF, delays apoptosis in IL-3–dependent pro-B cells deprived of growth factor. By contrast, in the present study, enforced expression of NFIL3 failed to protect M1p53tsval cells from p53-dependent apoptosis and actively antagonized the ability of IL-6 to rescue cells from that fate, consistent with its role as either a transcriptional repressor or activator, depending on the cell type in which it is expressed. We conclude that the E2A-HLF chimera abrogates p53-induced apoptosis in leukemic cells, possibly through the transcriptional modulation of cell death pathways that are activated by p53 in response to DNA damage. © 1998 by The American Society of Hematology.

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The Chimeric E2A-HLF Transcription Factor Abrogates p53-Induced Apoptosis in Myeloid Leukemia Cells

Blood ◽

10.1182/blood.v92.4.1397 ◽

1998 ◽

Vol 92 (4) ◽

pp. 1397-1405 ◽

Cited By ~ 19

Author(s):

Rachel A. Altura ◽

Takeshi Inukai ◽

Richard A. Ashmun ◽

Gerard P. Zambetti ◽

Martine F. Roussel ◽

...

Keyword(s):

Dna Damage ◽

Cell Death ◽

B Cells ◽

Growth Factor ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Leukemia Cells ◽

Wild Type ◽

Wild Type P53 ◽

Induced Apoptosis

Abstract Leukemic lymphoblasts expressing the E2A-HLF oncoprotein possess wild-type p53 genes, but do not undergo apoptosis in response to DNA damage. Experimentally, E2A-HLF prevents apoptosis due to growth factor deprivation or γ-irradiation in interleukin-3 (IL-3)–dependent murine pro-B cells. To directly test the chimeric protein’s ability to abrogate p53-mediated cell death, we used mouse myeloid leukemia cells (M1p53tsval) that constitutively express a temperature-sensitive (ts) mutant p53 gene and undergo apoptosis when p53 assumes an active wild-type configuration. This effect is blocked by treatment with IL-6, which allows the cells to survive in culture despite wild-type p53 activation. We introduced E2A-HLF into M1p53tsval cells and found that they were resistant to p53-mediated apoptosis and that E2A-HLF effectively substituted for the survival functions of IL-6. The expression of p53-responsive genes such as p21 and Bax was upregulated normally, suggesting that E2A-HLF acts downstream of p53 to block execution of the p53-induced apoptotic program. NFIL3, a growth factor-regulated bZIP protein that binds to the same DNA-consensus site as E2A-HLF, delays apoptosis in IL-3–dependent pro-B cells deprived of growth factor. By contrast, in the present study, enforced expression of NFIL3 failed to protect M1p53tsval cells from p53-dependent apoptosis and actively antagonized the ability of IL-6 to rescue cells from that fate, consistent with its role as either a transcriptional repressor or activator, depending on the cell type in which it is expressed. We conclude that the E2A-HLF chimera abrogates p53-induced apoptosis in leukemic cells, possibly through the transcriptional modulation of cell death pathways that are activated by p53 in response to DNA damage. © 1998 by The American Society of Hematology.

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