Genetic background determines the response to adenovirus-mediated wild-type p53 expression in pancreatic tumor cells

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

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Adenovirus-mediated wild-type P53 expression suppresses growth of lung adeno-carcinoma cells

Chinese Journal of Cancer Research ◽

10.1007/bf02948356 ◽

1998 ◽

Vol 10 (3) ◽

pp. 178-181

Author(s):

Jian Li ◽

Yongjing Xia ◽

Lei Jiang ◽

Hongxia Li ◽

Yajun Hu ◽

...

Keyword(s):

Carcinoma Cells ◽

Wild Type ◽

P53 Expression ◽

Wild Type P53 ◽

Adeno Carcinoma

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Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity

Molecular and Cellular Biology ◽

10.1128/mcb.00375-18 ◽

2018 ◽

Vol 39 (4) ◽

Cited By ~ 3

Author(s):

Leixiang Yang ◽

Tanjing Song ◽

Qian Cheng ◽

Lihong Chen ◽

Jiandong Chen

Keyword(s):

Tumor Cells ◽

Recent Work ◽

Intramolecular Interaction ◽

E3 Ligase ◽

Mutant P53 ◽

Wild Type ◽

Gain Of Function ◽

Core Domain ◽

Acidic Domain ◽

Wild Type P53

ABSTRACT Missense p53 mutants often accumulate in tumors and drive progression through gain of function. MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Here, we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity than wild-type p53. The mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme. An MDM2 construct with extra copies of the acidic domain is resistant to inhibition by mutant p53 and efficiently promotes mutant p53 ubiquitination and degradation. The results suggest that mutant p53 interferes with the intramolecular autoactivation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells.

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Tumor Eradication by Wild-type p53-specific Cytotoxic T Lymphocytes

Journal of Experimental Medicine ◽

10.1084/jem.186.5.695 ◽

1997 ◽

Vol 186 (5) ◽

pp. 695-704 ◽

Cited By ~ 149

Author(s):

Michel P.M. Vierboom ◽

Hans W. Nijman ◽

Rienk Offringa ◽

Ellen I.H. van der Voort ◽

Thorbald van Hall ◽

...

Keyword(s):

T Lymphocytes ◽

Tumor Cells ◽

Cytotoxic T Lymphocytes ◽

Normal Tissue ◽

P53 Protein ◽

P53 Gene ◽

Wild Type ◽

Wild Type P53 ◽

Tumor Outgrowth ◽

Tumor Eradication

The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 −/−) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.

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Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells

Nature Genetics ◽

10.1038/ng1094-171 ◽

1994 ◽

Vol 8 (2) ◽

pp. 171-176 ◽

Cited By ~ 215

Author(s):

Erwin G. Van Meir ◽

Peter J. Polverini ◽

Victoria R. Chazin ◽

H.-J. Su Huang ◽

Nicolas de Tribolet ◽

...

Keyword(s):

Wild Type ◽

Glioblastoma Cells ◽

P53 Expression ◽

Wild Type P53

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Endogenous p21WAF1/CIP1 status predicts the response of human tumor cells to wild-type p53 and p21WAF1/CIP1 overexpression

Cancer Gene Therapy ◽

10.1038/sj.cgt.7700588 ◽

2003 ◽

Vol 10 (6) ◽

pp. 457-467 ◽

Cited By ~ 23

Author(s):

Marijeta Kralj ◽

Koraljka Husnjak ◽

Tajana Körbler ◽

Jasminka Pavelić

Keyword(s):

Tumor Cells ◽

Human Tumor ◽

Wild Type ◽

Human Tumor Cells ◽

Wild Type P53

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Increased epidermal functioning wild-type p53 expression in vitiligo

Experimental Dermatology ◽

10.1034/j.1600-0625.2003.00084.x ◽

2003 ◽

Vol 12 (3) ◽

pp. 268-277 ◽

Cited By ~ 36

Author(s):

Karin U. Schallreuter ◽

Stefanie Behrens-Williams ◽

Tahira P. Khaliq ◽

Steven M. Picksley ◽

Eva M. J. Peters ◽

...

Keyword(s):

Wild Type ◽

P53 Expression ◽

Wild Type P53

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Abstract 2603: Specific growth suppression of wild-type p53 tumor cells by DNA-modified siRNA sequences targeting MDM2

10.1158/1538-7445.am2014-2603 ◽

2014 ◽

Author(s):

Mitsuaki Hirose ◽

Kenji Yamato ◽

Rie Saito ◽

Takunori Ueno ◽

Sachiko Hirai ◽

...

Keyword(s):

Tumor Cells ◽

Specific Growth ◽

Growth Suppression ◽

Wild Type ◽

Wild Type P53

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Expression of Wild-Type p53 by Curcumin, Alpinetin and Flavokawain B in Colorectal Cancer cells Expressing R273H Mutant p53

Nigerian Journal of Basic and Applied Sciences ◽

10.4314/njbas.v27i2.12 ◽

2020 ◽

Vol 27 (2) ◽

pp. 88-94

Author(s):

I. Malami ◽

A. Muhammad ◽

I.B. Abubakar ◽

A.M. Alhassan

Keyword(s):

Bioactive Compounds ◽

Mutant P53 ◽

Wild Type ◽

P53 Expression ◽

Gene And Protein Expression ◽

Colorectal Cancer Cells ◽

Binding Core ◽

Wild Type P53 ◽

Dose Dependent

A mutation in p53 is frequently reported in nearly 50% of all of human cancers arising from DNA-binding core domain of p53. DNA-contact mutant R273H rendered p53 at dysfunctional state due to the substitution of single residue Arg273 for His273. Here, natural bioactive compounds curcumin, alpinetin and flavokawain B were investigated for possible stabilisation of wild-type p53 expression in vitro using HT-29 cells harbouring R273H rendered p53. Accordingly, all the bioactive compounds were able to induce the expression of wild-type p53 both at the levels of gene and protein expression. A dose-dependent induction of p53 was evident at 12.5, 25 and 50 μM concentration. The present study has shown that the bioactive compounds may have restored the wild-type p53 functional activity in tumour cells expressing R273H mutant p53. Keywords: Curcumin, Alpinetin, Flavokawain B, p53, R273H

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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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