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.
162 - 167
Adenovirus E1A Proteins, Animals, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Blotting, Western, Breast Neoplasms, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Carrier Proteins, Cell Transformation, Neoplastic, Cisplatin, Drug Resistance, Female, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Regulation, Neoplastic, Genes, ras, Humans, In Vitro Techniques, Intracellular Signaling Peptides and Proteins, Microscopy, Fluorescence, Mutation, Oligonucleotides, Antisense, Osteosarcoma, RNA Interference, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Up-Regulation, src Homology Domains