Cisplatinum and taxol induce different patterns of p53 phosphorylation

Giovanna Damia, Laura Filiberti, Faina Vikhanskaya, Laura Carrassa, Yoichi Taya, Maurizio D'Incalci, Massimo Broggini

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Posttranslational modifications of p53 induced by two widely used anticancer agents, cisplatinum (DDP) and taxol were investigated in two human cancer cell lines. Although both drugs were able to induce phosphorylation at serine 20 (Ser20), only DDP treatment induced p53 phosphorylation at serine 15 (Ser15). Moreover, both drug treatments were able to increase p53 levels and consequently the transcription of wall and mdm-2 genes, although DDP treatment resulted in a stronger inducer of both genes. Using two ataxia telangiectasia mutated (ATM) cell lines, the role of ATM in drug-induced p53 phosphorylations was investigated. No differences in drug-induced p53 phosphorylation could be observed, indicating that ATM is not the kinase involved in these phosphorylation events. In addition, inhibition of DNA-dependent protein kinase activity by wortmannin did not abolish p53 phosphorylation at Ser15 and Ser20, again indicating that DNA-PK is unlikely to be the kinase involved. After both taxol and DDP treatments, an activation of hCHK2 was found and this is likely to be responsible for phosphorylation at Ser20. In contrast, only DDP was able to activate ATR, which is the candidate kinase for phosphorylation of Ser15 by this drug. This data clearly suggests that differential mechanisms are involved in phosphorylation and activation of p53 depending on the drug type.

Original languageEnglish
Pages (from-to)10-16
Number of pages7
JournalNeoplasia (United States)
Volume3
Issue number1
Publication statusPublished - 2001

Fingerprint

Paclitaxel
Phosphorylation
Serine
Ataxia Telangiectasia
Pharmaceutical Preparations
Phosphotransferases
DNA-Activated Protein Kinase
Cell Line
Protein-Serine-Threonine Kinases
Post Translational Protein Processing
Antineoplastic Agents
Genes
DNA

Keywords

  • Anticancer agents
  • Cell cycle
  • Checkpoints
  • p53
  • Phosphorylation

ASJC Scopus subject areas

  • Cancer Research

Cite this

Cisplatinum and taxol induce different patterns of p53 phosphorylation. / Damia, Giovanna; Filiberti, Laura; Vikhanskaya, Faina; Carrassa, Laura; Taya, Yoichi; D'Incalci, Maurizio; Broggini, Massimo.

In: Neoplasia (United States), Vol. 3, No. 1, 2001, p. 10-16.

Research output: Contribution to journalArticle

@article{546459cc1cd9487fba266da79654333c,
title = "Cisplatinum and taxol induce different patterns of p53 phosphorylation",
abstract = "Posttranslational modifications of p53 induced by two widely used anticancer agents, cisplatinum (DDP) and taxol were investigated in two human cancer cell lines. Although both drugs were able to induce phosphorylation at serine 20 (Ser20), only DDP treatment induced p53 phosphorylation at serine 15 (Ser15). Moreover, both drug treatments were able to increase p53 levels and consequently the transcription of wall and mdm-2 genes, although DDP treatment resulted in a stronger inducer of both genes. Using two ataxia telangiectasia mutated (ATM) cell lines, the role of ATM in drug-induced p53 phosphorylations was investigated. No differences in drug-induced p53 phosphorylation could be observed, indicating that ATM is not the kinase involved in these phosphorylation events. In addition, inhibition of DNA-dependent protein kinase activity by wortmannin did not abolish p53 phosphorylation at Ser15 and Ser20, again indicating that DNA-PK is unlikely to be the kinase involved. After both taxol and DDP treatments, an activation of hCHK2 was found and this is likely to be responsible for phosphorylation at Ser20. In contrast, only DDP was able to activate ATR, which is the candidate kinase for phosphorylation of Ser15 by this drug. This data clearly suggests that differential mechanisms are involved in phosphorylation and activation of p53 depending on the drug type.",
keywords = "Anticancer agents, Cell cycle, Checkpoints, p53, Phosphorylation",
author = "Giovanna Damia and Laura Filiberti and Faina Vikhanskaya and Laura Carrassa and Yoichi Taya and Maurizio D'Incalci and Massimo Broggini",
year = "2001",
language = "English",
volume = "3",
pages = "10--16",
journal = "Neoplasia",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "1",

}

TY - JOUR

T1 - Cisplatinum and taxol induce different patterns of p53 phosphorylation

AU - Damia, Giovanna

AU - Filiberti, Laura

AU - Vikhanskaya, Faina

AU - Carrassa, Laura

AU - Taya, Yoichi

AU - D'Incalci, Maurizio

AU - Broggini, Massimo

PY - 2001

Y1 - 2001

N2 - Posttranslational modifications of p53 induced by two widely used anticancer agents, cisplatinum (DDP) and taxol were investigated in two human cancer cell lines. Although both drugs were able to induce phosphorylation at serine 20 (Ser20), only DDP treatment induced p53 phosphorylation at serine 15 (Ser15). Moreover, both drug treatments were able to increase p53 levels and consequently the transcription of wall and mdm-2 genes, although DDP treatment resulted in a stronger inducer of both genes. Using two ataxia telangiectasia mutated (ATM) cell lines, the role of ATM in drug-induced p53 phosphorylations was investigated. No differences in drug-induced p53 phosphorylation could be observed, indicating that ATM is not the kinase involved in these phosphorylation events. In addition, inhibition of DNA-dependent protein kinase activity by wortmannin did not abolish p53 phosphorylation at Ser15 and Ser20, again indicating that DNA-PK is unlikely to be the kinase involved. After both taxol and DDP treatments, an activation of hCHK2 was found and this is likely to be responsible for phosphorylation at Ser20. In contrast, only DDP was able to activate ATR, which is the candidate kinase for phosphorylation of Ser15 by this drug. This data clearly suggests that differential mechanisms are involved in phosphorylation and activation of p53 depending on the drug type.

AB - Posttranslational modifications of p53 induced by two widely used anticancer agents, cisplatinum (DDP) and taxol were investigated in two human cancer cell lines. Although both drugs were able to induce phosphorylation at serine 20 (Ser20), only DDP treatment induced p53 phosphorylation at serine 15 (Ser15). Moreover, both drug treatments were able to increase p53 levels and consequently the transcription of wall and mdm-2 genes, although DDP treatment resulted in a stronger inducer of both genes. Using two ataxia telangiectasia mutated (ATM) cell lines, the role of ATM in drug-induced p53 phosphorylations was investigated. No differences in drug-induced p53 phosphorylation could be observed, indicating that ATM is not the kinase involved in these phosphorylation events. In addition, inhibition of DNA-dependent protein kinase activity by wortmannin did not abolish p53 phosphorylation at Ser15 and Ser20, again indicating that DNA-PK is unlikely to be the kinase involved. After both taxol and DDP treatments, an activation of hCHK2 was found and this is likely to be responsible for phosphorylation at Ser20. In contrast, only DDP was able to activate ATR, which is the candidate kinase for phosphorylation of Ser15 by this drug. This data clearly suggests that differential mechanisms are involved in phosphorylation and activation of p53 depending on the drug type.

KW - Anticancer agents

KW - Cell cycle

KW - Checkpoints

KW - p53

KW - Phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=0035093544&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035093544&partnerID=8YFLogxK

M3 - Article

C2 - 11326311

AN - SCOPUS:0035093544

VL - 3

SP - 10

EP - 16

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

IS - 1

ER -