RESUMEN
In this perspective I look back on the twists and turns that influenced the direction of my scientific career over the past 40 years. From my early ambition to be a chemist to my training in Philadelphia and Bethesda as a molecular biologist, I benefited enormously from generous and valuable mentoring. In my independent career in Philadelphia and Princeton, I was motivated by a keen interest in the changes in gene expression that direct the development of the mammalian embryo and inspired by the creativity and energy of my students, fellows, and research staff. After twelve years as President of Princeton University, I have happily returned to the faculty of the Department of Molecular Biology.
Asunto(s)
Biología Molecular/historia , Universidades/historia , Secuencia de Aminoácidos , Animales , Canadá , Paseo de Cromosoma , Desarrollo Embrionario/genética , Proteínas del Ojo/genética , Proteínas del Ojo/historia , Regulación del Desarrollo de la Expresión Génica , Impresión Genómica , Historia del Siglo XX , Historia del Siglo XXI , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/historia , Humanos , Ratones , Datos de Secuencia Molecular , National Institutes of Health (U.S.) , New Jersey , Factor de Transcripción PAX6 , Factores de Transcripción Paired Box/genética , Factores de Transcripción Paired Box/historia , Empalme del ARN , ARN Largo no Codificante/genética , ARN Largo no Codificante/historia , Proteínas Represoras/genética , Proteínas Represoras/historia , Estados Unidos , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/historia , Globinas beta/genética , Globinas beta/historiaRESUMEN
Herpesvirus Saimiri gene 13 (HVS13) exhibits 57% identity with the predicted sequence of a T cell-derived molecule termed CTLA8. Recombinant HVS13 and CTLA8 stimulate transcriptional factor NF-kappaB activity and Interleukin-6 (IL-6) secretion in fibroblasts, and costimulate T cell proliferation. An HVS13.Fc fusion protein was used to isolate a cDNA encoding a novel receptor that also binds CTLA8. This receptor is unrelated to previously identified cytokine receptor families. A recombinant soluble receptor inhibited T cell proliferation and IL-2 production induced by PHA, concanavalin A (conA), and anti-TCR MAb. These results define CTLA8 and HVS13 as novel cytokines that bind to a novel cytokine receptor. We propose to call these molecules IL-17, vIL-17, and IL-17R, respectively.
Asunto(s)
Herpesvirus Saimiriino 2/inmunología , Interleucina-17/historia , Receptores de Interleucina-17/historia , Proteínas Represoras/historia , Transactivadores/historia , Secuencia de Aminoácidos , Animales , Aotidae , Secuencia de Bases , Línea Celular Tumoral , Historia del Siglo XX , Humanos , Ratones , Datos de Secuencia Molecular , Unión Proteica/inmunología , RatasAsunto(s)
Linfocitos B/inmunología , Diferenciación Celular/inmunología , Factores de Transcripción/historia , Animales , Linfocitos B/metabolismo , Diferenciación Celular/genética , Línea Celular Tumoral , Clonación Molecular , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Ratones , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Represoras/historia , Homología Estructural de Proteína , Factores de Transcripción/genética , Factores de Transcripción/aislamiento & purificaciónRESUMEN
Few proteins have had such a strong impact on a field as the lac repressor has had in Molecular Biology. Over 40 years ago, Jacob and Monod [Genetic regulatory mechanisms in the synthesis of proteins, J. Mol. Biol. 3 (1961) 318] proposed a model for gene regulation, which survives essentially unchanged in contemporary textbooks. It is a cogent depiction of how a set of 'structural' genes may be coordinately transcribed in response to environmental conditions and regulates metabolic events in the cell. In bacteria, the genes required for lactose utilization are negatively regulated when a repressor molecule binds to an upstream cis activated operator. The repressor and its operator together form a genetic switch, the lac operon. The switch functions when inducer molecules alter the conformation of the repressor in a specific manner. In the presence of a particular metabolite, the repressor undergoes a conformational change that reduces its affinity for the operator. The structures of the lac repressor and its complexes with operator DNA and effector molecules have provided a physical platform for visualizing at the molecular level the different conformations the repressor and the molecular basis for the switch. The structures of lac repressor, bound to its operator and inducer, have also been invaluable for interpreting a plethora of biochemical and genetic data.