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Nat Med ; 24(3): 271-281, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29400712

RESUMO

Hedgehog pathway-dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to identify a noncanonical hedgehog activation pathway driven by the transcription factor serum response factor (SRF). Active SRF along with its coactivator megakaryoblastic leukemia 1 (MKL1) binds DNA near hedgehog target genes and forms a previously unknown protein complex with the hedgehog transcription factor glioma-associated oncogene family zinc finger-1 (GLI1), causing amplification of GLI1 transcriptional activity. We show that cytoskeletal activation through Rho and the formin family member Diaphanous (mDia) is required for SRF-MKL-driven GLI1 activation and for tumor cell viability. Remarkably, nuclear MKL1 staining served as a biomarker in tumors from mice and human subjects to predict tumor responsiveness to MKL inhibitors, highlighting the therapeutic potential of targeting this pathway. Thus, our study illuminates, for the first time, cytoskeletal-activation-driven transcription as a personalized therapeutic target for combatting drug-resistant malignancies.


Assuntos
Carcinoma Basocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Resposta Sérica/genética , Transativadores/genética , Proteína GLI1 em Dedos de Zinco/genética , Animais , Carcinoma Basocelular/genética , Carcinoma Basocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Proteínas Hedgehog , Humanos , Camundongos , Complexos Multiproteicos/genética , Transdução de Sinais , Ativação Transcricional
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