RESUMO
Tumor-associated mutants of the p53 tumor suppressor protein exert biological activities compatible with an oncogenic gain of function. To explore the underlying molecular mechanism, we performed microarray analysis, comparing p53-null cells to mutant p53-expressing cells. One of the genes up-regulated in the presence of mutant p53 was EGR1, a transcription factor implicated in growth control, apoptosis, and cancer. EGR1 induction by various types of stress is markedly augmented in cells expressing mutant p53. Moreover, chromatin immunoprecipitation analysis indicates that mutant p53 is physically associated with the EGR1 promoter. Functional assays indicate that induction of EGR1 by mutant p53 contributes to enhanced transformed properties and resistance to apoptosis. We propose that EGR1 is a significant contributor to mutant p53 gain of function.
Assuntos
Proteínas de Ligação a DNA/genética , Genes p53 , Proteínas Imediatamente Precoces/genética , Fatores de Transcrição/genética , Ativação Transcricional/genética , Sequência de Bases , Linhagem Celular , Primers do DNA , Proteína 1 de Resposta de Crescimento Precoce , Humanos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
Tumor-associated mutant forms of p53 can exert an antiapoptotic gain of function activity, which probably confers a selective advantage upon tumor cells harboring such mutations. We report that mutant p53 suppresses the expression of the CD95 (Fas/APO-1) gene, encoding a death receptor implicated in a variety of apoptotic responses. Moderate (40-50%) downregulation of CD95 mRNA and surface protein expression by mutant p53 correlates with partial protection against CD95-dependent cell death. Excess mutant p53 represses the transcriptional activity of the CD95 promoter, with the extent of repression varying among different tumor-associated p53 mutants. Furthermore, mutant p53 protein binds the CD95 promoter in vitro, in a region distinct from the one implicated in tight interactions of the CD95 gene with wild-type p53. Hence, the CD95 promoter is likely to be a direct target for downregulation by mutant p53. This activity of mutant p53 may contribute to its gain of function effects in oncogenesis.
