iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human

Daniele Bergamaschi; Yardena Samuels; Nigel J O'Neil; Giuseppe Trigiante; Tim Crook; Jung-Kuang Hsieh; Daniel J O'Connor; Shan Zhong; Isabelle Campargue; Matthew L Tomlinson; Patricia E Kuwabara; Xin Lu

doi:10.1038/ng1070

iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human

Nat Genet. 2003 Feb;33(2):162-7. doi: 10.1038/ng1070. Epub 2003 Jan 13.

Authors

Daniele Bergamaschi¹, Yardena Samuels, Nigel J O'Neil, Giuseppe Trigiante, Tim Crook, Jung-Kuang Hsieh, Daniel J O'Connor, Shan Zhong, Isabelle Campargue, Matthew L Tomlinson, Patricia E Kuwabara, Xin Lu

Affiliation

¹ Ludwig Institute for Cancer Research, Imperial College School of Medicine, St. Mary's Campus, Norfolk Place, London, W2 1PG, UK.

PMID: 12524540
DOI: 10.1038/ng1070

Abstract

We have previously shown that ASPP1 and ASPP2 are specific activators of p53; one mechanism by which wild-type p53 is tolerated in human breast carcinomas is through loss of ASPP activity. We have further shown that 53BP2, which corresponds to a C-terminal fragment of ASPP2, acts as a dominant negative inhibitor of p53 (ref. 1). Hence, an inhibitory form of ASPP resembling 53BP2 could allow cells to bypass the tumor-suppressor functions of p53 and the ASPP proteins. Here, we characterize such a protein, iASPP (inhibitory member of the ASPP family), encoded by PPP1R13L in humans and ape-1 in Caenorhabditis elegans. iASPP is an evolutionarily conserved inhibitor of p53; inhibition of iASPP by RNA-mediated interference or antisense RNA in C. elegans or human cells, respectively, induces p53-dependent apoptosis. Moreover, iASPP is an oncoprotein that cooperates with Ras, E1A and E7, but not mutant p53, to transform cells in vitro. Increased expression of iASPP also confers resistance to ultraviolet radiation and to cisplatin-induced apoptosis. iASPP expression is upregulated in human breast carcinomas expressing wild-type p53 and normal levels of ASPP. Inhibition of iASPP could provide an important new strategy for treating tumors expressing wild-type p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenovirus E1A Proteins / physiology
Animals
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Apoptosis / physiology*
Apoptosis / radiation effects
Apoptosis Regulatory Proteins
Blotting, Western
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Caenorhabditis elegans / genetics
Caenorhabditis elegans / metabolism*
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / metabolism*
Carrier Proteins / antagonists & inhibitors*
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Transformation, Neoplastic
Cisplatin / pharmacology
Drug Resistance / genetics
Female
Flow Cytometry
Fluorescent Antibody Technique
Gene Expression Regulation, Neoplastic
Genes, ras / physiology
Humans
In Vitro Techniques
Intracellular Signaling Peptides and Proteins*
Microscopy, Fluorescence
Mutation
Oligonucleotides, Antisense / pharmacology
Osteosarcoma / genetics
Osteosarcoma / metabolism*
RNA Interference
Repressor Proteins
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
Up-Regulation
src Homology Domains / physiology

Substances

Adenovirus E1A Proteins
Antineoplastic Agents
Apoptosis Regulatory Proteins
CEP-1 protein, C elegans
Caenorhabditis elegans Proteins
Carrier Proteins
Intracellular Signaling Peptides and Proteins
Oligonucleotides, Antisense
PPP1R13L protein, human
Repressor Proteins
TP53BP2 protein, human
Transcription Factors
Tumor Suppressor Protein p53
Cisplatin