RESUMO
Histone monoubiquitylation is implicated in critical regulatory processes. We explored the roles of histone H2B ubiquitylation in human cells by reducing the expression of hBRE1/RNF20, the major H2B-specific E3 ubiquitin ligase. While H2B ubiquitylation is broadly associated with transcribed genes, only a subset of genes was transcriptionally affected by RNF20 depletion and abrogation of H2B ubiquitylation. Gene expression dependent on RNF20 includes histones H2A and H2B and the p53 tumor suppressor. In contrast, RNF20 suppresses the expression of several proto-oncogenes, which reside preferentially in closed chromatin and are modestly transcribed despite bearing marks usually associated with high transcription rates. Remarkably, RNF20 depletion augmented the transcriptional effects of epidermal growth factor (EGF), increased cell migration, and elicited transformation and tumorigenesis. Furthermore, frequent RNF20 promoter hypermethylation was observed in tumors. RNF20 may thus be a putative tumor suppressor, acting through selective regulation of a distinct subset of genes.
Assuntos
Histonas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Movimento Celular , Transformação Celular Neoplásica , Cromatina/genética , Cromatina/metabolismo , Metilação de DNA , DNA de Neoplasias/química , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células HeLa , Histonas/química , Humanos , Camundongos , Camundongos Nus , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , RNA Interferente Pequeno/genética , Supressão Genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
In the course of the last several years, microRNAs (miRNAs) have become a focus of great interest, owing to their unsuspected important roles in the regulation of many critical biological processes. Not surprisingly, miRNAs are also turning out to be intimately involved in cancer, through either excessive or decreased activity. A series of recent studies reveal a close link between miRNAs and the p53 tumor suppressor: as a transcription factor, p53 controls the expression of specific miRs, and this additional capacity of p53 contributes to its biological activities. This review will discuss the recent studies and their implications.
Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , MicroRNAs/genéticaRESUMO
p53 is a potent tumor suppressor, whose biological effects are largely due to its function as a transcriptional regulator. Here we report that, in addition to regulating the expression of hundreds of protein-coding genes, p53 also modulates the levels of microRNAs (miRNAs). Specifically, p53 can induce expression of microRNA-34a (miR-34a) in cultured cells as well as in irradiated mice, by binding to a perfect p53 binding site located within the gene that gives rise to miR-34a. Processing of the primary transcript into mature miR-34a involves the excision of a 30 kb intron. Notably, inactivation of miR-34a strongly attenuates p53-mediated apoptosis in cells exposed to genotoxic stress, whereas overexpression of miR-34a mildly increases apoptosis. Hence, miR-34a is a direct proapoptotic transcriptional target of p53 that can mediate some of p53's biological effects. Perturbation of miR-34a expression, as occurs in some human cancers, may thus contribute to tumorigenesis by attenuating p53-dependent apoptosis.
