Gene expression profiling of isogenic cells with different TP53 gene dosage reveals numerous genes that are affected by TP53 dosage and identifies CSPG2 as a direct target of p53

摘要: TP53 does not fully comply with the Knudson model [Knudson, A. G., Jr. (1971) Proc. Natl. Acad. Sci. USA 68, 820–823] in that a reduction of constitutional expression p53 may be sufficient for tumor predisposition . This finding suggests gene-dosage effect function. To determine whether gene dosage affects transcriptional regulation target genes, we performed oligonucleotide-array analysis by using human cells wild-type (p53 +/+), or one +/−), both −/−) alleles disrupted homologous recombination. We identified 35 genes whose is significantly correlated to TP53. These are involved variety cellular processes including signal transduction, cell adhesion, and transcription regulation. Several them neurogenesis neural crest migration, developmental which known play role. Motif search revealed highly expressed +/+ +/− cells, several contain putative consensus binding site (bs), suggesting they could directly regulated p53. Among those chose CSPG2 (which encodes versican) further study because it contains bona fide bs its first intron correlates dosage. By vitro vivo assays, showed transactivated In conclusion, developed strategy demonstrate many affected their expression. report candidate as potential downstream targets nonstressed cells. them, validated being Our method provides useful tool elucidate additional mechanisms exerts functions.