RESUMO
Extensive studies have shown that p53 is important in tumour prevention. However, little is known about its normal physiological function. Here we show that p53 is important in reproduction, in a gender-specific manner. Significant decreases in embryonic implantation, pregnancy rate and litter size were observed in matings with p53-/- female mice but not with p53-/- male mice. The gene encoding leukaemia inhibitory factor (LIF), a cytokine critical for implantation, was identified as a p53-regulated gene that functions as the downstream mediator of this effect. p53 can regulate both basal and inducible transcription of LIF. Loss of p53 decreased both the level and function of LIF in uteri. Lower LIF levels were observed in the uteri of p53-/- mice than in those of p53+/+ mice, particularly at day 4 of pregnancy, when transiently induced high levels of LIF were crucial for embryonic implantation. This observation probably accounts for the impaired implantation of embryos in p53-/- female mice. Administration of LIF to pregnant p53-/- mice restored maternal reproduction by improving implantation. These results demonstrate a function for p53 in maternal reproduction through the regulation of LIF. Evidence is accumulating that p53 may have a similar function in humans.
Assuntos
Fator Inibidor de Leucemia/metabolismo , Mães , Reprodução/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência Consenso/genética , Implantação do Embrião/genética , Feminino , Regulação da Expressão Gênica , Genes p53/genética , Genótipo , Fator Inibidor de Leucemia/deficiência , Fator Inibidor de Leucemia/genética , Tamanho da Ninhada de Vivíparos/genética , Tamanho da Ninhada de Vivíparos/fisiologia , Masculino , Camundongos , Gravidez/genética , Gravidez/fisiologia , Reprodução/genética , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Útero/metabolismoRESUMO
The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the beta1 and beta2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal-specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways.
Assuntos
Regulação Neoplásica da Expressão Gênica , Fator de Crescimento Insulin-Like I/metabolismo , PTEN Fosfo-Hidrolase/biossíntese , Proteínas Quinases/biossíntese , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Proteínas Supressoras de Tumor/biossíntese , Proteínas Quinases Ativadas por AMP , Proteínas E1B de Adenovirus/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Glucose/deficiência , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/biossíntese , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Complexos Multienzimáticos , Especificidade de Órgãos , PTEN Fosfo-Hidrolase/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases , Transdução de Sinais , Serina-Treonina Quinases TOR , Proteína 2 do Complexo Esclerose Tuberosa , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas ras/metabolismoRESUMO
Cancer is a disease of aging. The accumulation of mutations in individual cells over a lifetime is thought to be the reason. In this work, we explored an additional hypothesis: could p53 function decline with age, which would contribute to an enhanced mutation frequency and tumorigenesis in the aging process? The efficiency of the p53 response to gamma-irradiation was found to decline significantly in various tissues of aging mice from several inbred strains, including lower p53 transcriptional activity and p53-dependent apoptosis. This decline resulted from a decreased stabilization of the p53 protein after stress. The function of the Ataxia-telangiectasia mutated (ATM) kinase declined significantly with age, which may then be responsible for the decline of the p53 response to radiation. Declining p53 responses to other stresses were also observed in the cultured splenocytes from aging mice. Interestingly, the time of onset of this decreased p53 response correlated with the life span of mice; mice that live longer delay their onset of decreased p53 activity with time. These results suggest an enhanced fixation of mutations in older individuals because of the declining fidelity of p53-mediated apoptosis or senescence in response to stress, and they suggest a plausible explanation for the correlation between tumorigenesis and the aging process.