Identification of STAG1 as a key mediator of a p53-dependent apoptotic pathway.
A mutant version of p53 (p53-121F), in which phenylalanine replaces the 121st serine residue, can induce apoptosis more effectively than wild-type p53 (wt-p53). In view of this observation, we considered that one or more apoptosis-related p53-target genes might be preferentially induced by p53-121F. We carried out cDNA microarray analysis to identify such genes, using mRNAs isolated from LS174T colon-cancer cells infected by adenovirus vectors containing either p53-121F (Ad-p53-121F) or wt-p53 (Ad-p53). The STAG1 gene was one of the transcripts showing higher expression levels in cells infected with Ad-p53-121F as opposed to Ad-wtp53. The encoded product appears to contain a transmembrane domain, and binding motifs for SH3 and WW. In two other cancer cell lines, the expression of STAG1 mRNA was induced in response to various genotoxic stresses in a p53-dependent manner; moreover, enforced expression of STAG1 led to apoptosis in several additional cancer cell lines. Suppression of endogenous STAG1 using the RNA-interference method reduced the apoptotic response, whether induced by Ad-p53-121F or Ad-p53. These results suggest that STAG1, a novel transcriptional target for p53, mediates p53-dependent apoptosis, and might be a good candidate for next-generation gene therapy.
Anazawa
Yoshio
Y
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai Minato-ku, Tokyo 108-8639, Japan.
Arakawa
Hirofumi
H
Nakagawa
Hidewaki
H
Nakamura
Yusuke
Y
D019943:Amino Acid Substitution; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D009687:Nuclear Proteins; C108522:STAG1 protein, human; D016159:Tumor Suppressor Protein p53