RESUMO
The last 40 years have witnessed how p53 rose from a viral binding protein to a central factor in both stress responses and tumor suppression. The exquisite regulation of p53 functions is of vital importance for cell fate decisions. Among the multiple layers of mechanisms controlling p53 function, posttranslational modifications (PTMs) represent an efficient and precise way. Major p53 PTMs include phosphorylation, ubiquitination, acetylation, and methylation. Meanwhile, other PTMs like sumoylation, neddylation, O-GlcNAcylation, adenosine diphosphate (ADP)-ribosylation, hydroxylation, and ß-hydroxybutyrylation are also shown to play various roles in p53 regulation. By independent action or interaction, PTMs affect p53 stability, conformation, localization, and binding partners. Deregulation of the PTM-related pathway is among the major causes of p53-associated developmental disorders or diseases, especially in cancers. This review focuses on the roles of different p53 modification types and shows how these modifications are orchestrated to produce various outcomes by modulating p53 activities or targeted to treat different diseases caused by p53 dysregulation.
Assuntos
Neoplasias/genética , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , História do Século XX , História do Século XXI , Humanos , Neoplasias/história , Neoplasias/patologia , Estabilidade Proteica , Proteína Supressora de Tumor p53/históriaAssuntos
Biologia Molecular/história , Proteínas Proto-Oncogênicas c-mdm2 , Proteína Supressora de Tumor p53 , História do Século XX , História do Século XXI , Biologia Molecular/educação , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/história , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/história , Proteína Supressora de Tumor p53/metabolismoAssuntos
Distinções e Prêmios , Pesquisa Biomédica/história , Oncologia/história , Neoplasias/história , Proteína Supressora de Tumor p53/história , Perfilação da Expressão Gênica/história , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , História do Século XXI , Humanos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/terapia , Fenótipo , Prognóstico , Proteína Supressora de Tumor p53/genéticaAssuntos
Proteína Supressora de Tumor p53/história , Animais , Antígenos Transformantes de Poliomavirus/metabolismo , História do Século XX , História do Século XXI , Humanos , Camundongos , Oncogenes , Revisão da Pesquisa por Pares , Filogenia , Ligação Proteica , RNA/metabolismo , Vírus 40 dos Símios/metabolismoRESUMO
Thirty years of research on the p53 family of genes has generated almost fifty thousand publications. The first of these papers detected the p53 protein associated with a viral oncogene product in transformed cells and tumors and focused the field on cancer biology. Subsequent manuscripts have shown a wide variety of functions for the p53 family of genes and their proteins. These proteins are involved in reproduction, genomic repair, fidelity and recombination, the regulation of metabolic processes, longevity, surveillance of the stability of development, the production of stem cells and changes in epigenetic marks, the development of the nervous system (p73), the immune system (p73) and skin (p63), as well as the better known roles for the family in tumor suppression. The p53 family of genes has been found in the modern day ancestors of organisms with over one billion years of evolutionary history where they play a role in germ-line fidelity over that time span. As the body plan of the vertebrates emerged with the regeneration of tissues by stem cells over a lifetime, the p53 gene and its protein were adapted to be a tumor suppressor of somatic stem and progenitor cells complementing its' past functions in the germ line. Because the p53 family of genes has played a role in germ-line fidelity and preservation of the species, even in times of stress, these genes have been under constant selection pressure to change and adapt to new situations. This has given rise to this diversity of functions all working to preserve homeostatic processes that permit growth and reproduction in a world that is constantly challenging the fidelity of information transfer at each generation. The p53 family of gene products has influenced the rates of evolutionary change, just as evolutionary changes have altered the p53 family and its functions.
Assuntos
Família Multigênica , Pesquisa , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/história , Proteína Supressora de Tumor p53/fisiologia , Processamento Alternativo/genética , História do Século XX , História do Século XXI , NF-kappa B/metabolismo , Isoformas de Proteínas/genéticaRESUMO
Among the 278,092 publications indexed into PubMed in 1979, a handful of articles stand out as the foundation of one of the most profound forays into the molecular basis of carcinogenesis: the discovery of the p53 tumour-suppressor protein. In the 30 years since then, understanding of p53 has progressed from obscure oncogene to key tumour-suppressor gene with clinical potential. Yet, p53 research has not followed a straight course. In this Historical Review, we describe how the 1979 discovery has shaped our view of the molecular basis of cancer, and identify some crucial steps ahead to transfer the wealth of knowledge accumulated on p53 into applications to cancer prevention and treatment.