Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Science ; 378(6620): eabn5647, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36356142

RESUMO

T cells are the major arm of the immune system responsible for controlling and regressing cancers. To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) T cells. Top hits were MED12 and CCNC, components of the Mediator kinase module. Targeted MED12 deletion enhanced antitumor activity and sustained the effector phenotype in CAR- and T cell receptor-engineered T cells, and inhibition of CDK8/19 kinase activity increased expansion of nonengineered T cells. MED12-deficient T cells manifested increased core Meditator chromatin occupancy at transcriptionally active enhancers-most notably for STAT and AP-1 transcription factors-and increased IL2RA expression and interleukin-2 sensitivity. These results implicate Mediator in T cell effector programming and identify the kinase module as a target for enhancing potency of antitumor T cell responses.


Assuntos
Ciclina C , Complexo Mediador , Neoplasias , Receptores de Antígenos Quiméricos , Linfócitos T , Humanos , Quinase 8 Dependente de Ciclina/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Complexo Mediador/genética , Linfócitos T/imunologia , Fatores de Transcrição/genética , Estudo de Associação Genômica Ampla , Ciclina C/genética , Testes Genéticos , Imunoterapia Adotiva , Neoplasias/imunologia , Neoplasias/terapia
2.
Chem Biol ; 22(7): 946-56, 2015 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-26165154

RESUMO

Small protein ligands can provide superior physiological distribution compared with antibodies, and improved stability, production, and specific conjugation. Systematic evaluation of the PDB identified a scaffold to push the limits of small size and robust evolution of stable, high-affinity ligands: 45-residue T7 phage gene 2 protein (Gp2) contains an α helix opposite a ß sheet with two adjacent loops amenable to mutation. De novo ligand discovery from 10(8) mutants and directed evolution toward four targets yielded target-specific binders with affinities as strong as 200 ± 100 pM, Tms from 65 °C ± 3 °C to 80°C ± 1 °C, and retained activity after thermal denaturation. For cancer targeting, a Gp2 domain for epidermal growth factor receptor was evolved with 18 ± 8 nM affinity, receptor-specific binding, and high thermal stability with refolding. The efficiency of evolving new binding function and the size, affinity, specificity, and stability of evolved domains render Gp2 a uniquely effective ligand scaffold.


Assuntos
Aminoácidos/química , Receptores ErbB/metabolismo , Engenharia de Proteínas/métodos , Aminoácidos/metabolismo , Bases de Dados de Proteínas , Receptores ErbB/química , Receptores ErbB/genética , Humanos , Ligantes , Modelos Moleculares , Mutação , Ligação Proteica , Estrutura Terciária de Proteína , Especificidade por Substrato
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...