A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo

Helen S. Bell, Christine Dufès, Jim O'Prey, Diane Crighton, Daniele Bergamaschi, Xin Lu, Andreas G. Schätzlein, Karen H. Vousden, Kevin Ryan

Research output: Contribution to journalArticle

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Abstract

The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP - a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.
LanguageEnglish
Pages1008-1018
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number4
DOIs
StatePublished - 2 Apr 2007

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Peptides
Neoplasms
Null Lymphocytes
Helper-Inducer T-Lymphocytes
Transgenes
Nanoparticles
Transcriptional Activation
Cell Death
Gene Expression
Therapeutics

Keywords

  • photodynamic therapy
  • protoporphyrin IX
  • aminolevulinic acid
  • apoptosis
  • gene therapy
  • cancer
  • tumors
  • tumor suppressor p53
  • pharmacology
  • cancer therapy
  • cancer research

Cite this

Bell, H. S., Dufès, C., O'Prey, J., Crighton, D., Bergamaschi, D., Lu, X., ... Ryan, K. (2007). A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo. Journal of Clinical Investigation , 117(4), 1008-1018. DOI: 10.1172/JCI28920
Bell, Helen S. ; Dufès, Christine ; O'Prey, Jim ; Crighton, Diane ; Bergamaschi, Daniele ; Lu, Xin ; Schätzlein, Andreas G. ; Vousden, Karen H. ; Ryan, Kevin. / A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo. In: Journal of Clinical Investigation . 2007 ; Vol. 117, No. 4. pp. 1008-1018
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abstract = "The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP - a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.",
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Bell, HS, Dufès, C, O'Prey, J, Crighton, D, Bergamaschi, D, Lu, X, Schätzlein, AG, Vousden, KH & Ryan, K 2007, 'A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo' Journal of Clinical Investigation , vol. 117, no. 4, pp. 1008-1018. DOI: 10.1172/JCI28920

A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo. / Bell, Helen S.; Dufès, Christine; O'Prey, Jim; Crighton, Diane; Bergamaschi, Daniele; Lu, Xin; Schätzlein, Andreas G.; Vousden, Karen H.; Ryan, Kevin.

In: Journal of Clinical Investigation , Vol. 117, No. 4, 02.04.2007, p. 1008-1018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo

AU - Bell,Helen S.

AU - Dufès,Christine

AU - O'Prey,Jim

AU - Crighton,Diane

AU - Bergamaschi,Daniele

AU - Lu,Xin

AU - Schätzlein,Andreas G.

AU - Vousden,Karen H.

AU - Ryan,Kevin

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N2 - The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP - a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.

AB - The tumor suppressor p53 is a potent inducer of tumor cell death, and strategies exist to exploit p53 for therapeutic gain. However, because about half of human cancers contain mutant p53, application of these strategies is restricted. p53 family members, in particular p73, are in many ways functional paralogs of p53, but are rarely mutated in cancer. Methods for specific activation of p73, however, remain to be elucidated. We describe here a minimal p53-derived apoptotic peptide that induced death in multiple cell types regardless of p53 status. While unable to activate gene expression directly, this peptide retained the capacity to bind iASPP - a common negative regulator of p53 family members. Concordantly, in p53-null cells, this peptide derepressed p73, causing p73-mediated gene activation and death. Moreover, systemic nanoparticle delivery of a transgene expressing this peptide caused tumor regression in vivo via p73. This study therefore heralds what we believe to be the first strategy to directly and selectively activate p73 therapeutically and may lead to the development of broadly applicable agents for the treatment of malignant disease.

KW - photodynamic therapy

KW - protoporphyrin IX

KW - aminolevulinic acid

KW - apoptosis

KW - gene therapy

KW - cancer

KW - tumors

KW - tumor suppressor p53

KW - pharmacology

KW - cancer therapy

KW - cancer research

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DO - 10.1172/JCI28920

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VL - 117

SP - 1008

EP - 1018

JO - Journal of Clinical Investigation

T2 - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 4

ER -

Bell HS, Dufès C, O'Prey J, Crighton D, Bergamaschi D, Lu X et al. A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo. Journal of Clinical Investigation . 2007 Apr 2;117(4):1008-1018. Available from, DOI: 10.1172/JCI28920