RESUMO
The p53 tumor suppressor plays a key role in maintaining cellular integrity. In response to diverse stress signals, p53 can trigger apoptosis to eliminate damaged cells or cell-cycle arrest to enable cells to cope with stress and survive. However, the transcriptional networks underlying p53 pro-survival function are incompletely understood. Here, we show that in oncogenic-Ras-expressing cells, p53 promotes oxidative phosphorylation (OXPHOS) and cell survival upon glucose starvation. Analysis of p53 transcriptional activation domain mutants reveals that these responses depend on p53 transactivation function. Using gene expression profiling and ChIP-seq analysis, we identify several p53-inducible fatty acid metabolism-related genes. One such gene, Acad11, encoding a protein involved in fatty acid oxidation, is required for efficient OXPHOS and cell survival upon glucose starvation. This study provides new mechanistic insight into the pro-survival function of p53 and suggests that targeting this pathway may provide a strategy for therapeutic intervention based on metabolic perturbation.
Assuntos
Acil-CoA Desidrogenase/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acil-CoA Desidrogenase/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Redes Reguladoras de Genes , Glucose/farmacologia , Humanos , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Estrutura Terciária de Proteína , Interferência de RNA , Alinhamento de Sequência , Estresse Fisiológico , Ativação Transcricional , Transplante Heterólogo , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genéticaRESUMO
p53 is a crucial tumour suppressor that responds to diverse stress signals by orchestrating specific cellular responses, including transient cell cycle arrest, cellular senescence and apoptosis, which are all processes associated with tumour suppression. However, recent studies have challenged the relative importance of these canonical cellular responses for p53-mediated tumour suppression and have highlighted roles for p53 in modulating other cellular processes, including metabolism, stem cell maintenance, invasion and metastasis, as well as communication within the tumour microenvironment. In this Opinion article, we discuss the roles of classical p53 functions, as well as emerging p53-regulated processes, in tumour suppression.
Assuntos
Genes Supressores de Tumor , Neoplasias/genética , Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Senescência Celular , Dano ao DNA , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Transdução de Sinais , Células-Tronco/metabolismo , Transcrição Gênica , Ativação Transcricional , Proteína Supressora de Tumor p53/genéticaRESUMO
The mechanisms by which the p53 tumor suppressor acts remain incompletely understood. To gain new insights into p53 biology, we used high-throughput sequencing to analyze global p53 transcriptional networks in primary mouse embryo fibroblasts in response to DNA damage. Chromatin immunoprecipitation sequencing reveals 4785 p53-bound sites in the genome located near 3193 genes involved in diverse biological processes. RNA sequencing analysis shows that only a subset of p53-bound genes is transcriptionally regulated, yielding a list of 432 p53-bound and regulated genes. Interestingly, we identify a host of autophagy genes as direct p53 target genes. While the autophagy program is regulated predominantly by p53, the p53 family members p63 and p73 contribute to activation of this autophagy gene network. Induction of autophagy genes in response to p53 activation is associated with enhanced autophagy in diverse settings and depends on p53 transcriptional activity. While p53-induced autophagy does not affect cell cycle arrest in response to DNA damage, it is important for both robust p53-dependent apoptosis triggered by DNA damage and transformation suppression by p53. Together, our data highlight an intimate connection between p53 and autophagy through a vast transcriptional network and indicate that autophagy contributes to p53-dependent apoptosis and cancer suppression.
Assuntos
Autofagia/genética , Dano ao DNA/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , Animais , Pontos de Checagem do Ciclo Celular/genética , Sobrevivência Celular/genética , Células Cultivadas , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/genética , Estudo de Associação Genômica Ampla , Camundongos , Ligação Proteica , Análise de Sequência de RNARESUMO
p53 is a pivotal tumor suppressor that induces apoptosis, cell-cycle arrest and senescence in response to stress signals. Although p53 transcriptional activation is important for these responses, the mechanisms underlying tumor suppression have been elusive. To date, no single or compound mouse knockout of specific p53 target genes has recapitulated the dramatic tumor predisposition that characterizes p53-null mice. Recently, however, analysis of knock-in mice expressing p53 transactivation domain mutants has revealed a group of primarily novel direct p53 target genes that may mediate tumor suppression in vivo. We present here an overview of well-known p53 target genes and the tumor phenotypes of the cognate knockout mice, and address the recent identification of new p53 transcriptional targets and how they enhance our understanding of p53 transcriptional networks central for tumor suppression.
Assuntos
Redes Reguladoras de Genes , Neoplasias/metabolismo , Neoplasias/patologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose , Humanos , Neoplasias/genética , Ativação Transcricional , Proteína Supressora de Tumor p53/genéticaRESUMO
The link between EBV infection and Burkitt lymphoma (BL) is strong, but the mechanism underlying that link has been elusive. We have developed a mouse model for EBV-associated BL in which LMP2A, an EBV latency protein, and MYC are expressed in B cells. Our model has demonstrated the ability of LMP2A to accelerate tumor onset, increase spleen size, and bypass p53 inactivation. Here we describe the results of total gene expression analysis of tumor and pretumor B cells from our transgenic mouse model. Although we see many phenotypic differences and changes in gene expression in pretumor B cells, the transcriptional profiles of tumor cells from LMP2A/λ-MYC and λ-MYC mice are strikingly similar, with fewer than 20 genes differentially expressed. We evaluated the functional significance of one of the most interesting differentially expressed genes, Egr1, and found that it was not required for acceleration of tumor onset by LMP2A. Our studies demonstrate the remarkable ability of LMP2A to affect the pretumor B-cell phenotype and tumorigenesis without substantially altering gene expression in tumor cells.
Assuntos
Linfoma de Burkitt/genética , Linfoma de Burkitt/virologia , Perfilação da Expressão Gênica , Herpesvirus Humano 4/fisiologia , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Linfócitos B/virologia , Linfoma de Burkitt/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Genes myc/genética , Herpesvirus Humano 4/genética , Interações Hospedeiro-Patógeno , Humanos , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Leucossialina/genética , Leucossialina/metabolismo , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Baço/patologia , Baço/virologia , Proteínas da Matriz Viral/genéticaRESUMO
Burkitt's lymphoma (BL) is characterized by translocation of the MYC gene to an immunoglobulin locus. Transgenic mouse models have been used to study the molecular changes that are necessary to bypass tumor suppression in the presence of translocated MYC. Inactivation of the p53 pathway is a major step to tumor formation in mouse models that is also seen in human disease. Human BL is often highly associated with Epstein-Barr virus (EBV). The EBV latency protein latent membrane protein 2A (LMP2A) is known to promote B cell survival by affecting levels of pro-survival factors. Using LMP2A transgenic mouse models, we have identified a novel mechanism that permits lymphomagenesis in the presence of an intact p53 pathway. This work uncovers a contribution of EBV to molecular events that have documented importance in BL pathogenesis, and may underlie the poorly understood link between EBV and BL.
Assuntos
Linfoma de Burkitt/virologia , Herpesvirus Humano 4/metabolismo , Proteínas da Matriz Viral/fisiologia , Animais , Apoptose , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas da Matriz Viral/metabolismoRESUMO
Although Epstein-Barr virus (EBV) is linked to Burkitt's lymphoma (BL), the role of the virus in lymphomagenesis is unclear. LMP2A, encoded by EBV, can be detected in BL biopsies and has prosurvival functions. We generated mice expressing MYC and LMP2A in B cells. LMP2A/lambda-MYC mice show greatly accelerated tumor onset. Similar to previous work, we found p53 mutations in lambda-MYC tumors; however, we detected no mutations in the rapidly arising LMP2A/lambda-MYC tumors. We further demonstrate that the p53 pathway is functionally intact in LMP2A/lambda-MYC tumors, which have increased levels of PUMA and sensitivity to p53 activation by Nutlin. This work shows that LMP2A can permit tumorigenesis in the presence of an intact p53 pathway, identifying an important contribution of EBV to BL.