RESUMEN

Dysregulation of the NF-κB transcription factor occurs in many cancer types. Krüppel-like family of transcription factors (KLFs) regulate the expression of genes involved in cell proliferation, differentiation and survival. Here, we report a new mechanism of NF-κB activation in glioblastoma through depletion of the KLF6 tumor suppressor. We show that KLF6 transactivates multiple genes negatively controlling the NF-κB pathway and consequently reduces NF-κB nuclear localization and downregulates NF-κB targets. Reconstitution of KLF6 attenuates their malignant phenotype and induces neural-like differentiation and senescence, consistent with NF-κB pathway inhibition. KLF6 is heterozygously deleted in 74.5% of the analyzed glioblastomas and predicts unfavorable patient prognosis suggesting that haploinsufficiency is a clinically relevant means of evading KLF6-dependent regulation of NF-κB. Together, our study identifies a new mechanism by which KLF6 regulates NF-κB signaling, and how this mechanism is circumvented in glioblastoma through KLF6 loss.

Asunto(s)

Eliminación de Gen , Glioblastoma/genética , Glioblastoma/metabolismo , Haploinsuficiencia , Factores de Transcripción de Tipo Kruppel/genética , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas/genética , Transducción de Señal/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Glioblastoma/terapia , Humanos , Factor 6 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , FN-kappa B/genética , Proteínas Proto-Oncogénicas/metabolismo , Activación Transcripcional

RESUMEN

We report the design and experimental realization of a new type of microring filters consisting of two parallel-cascaded microring doublets connected by a π-phase shift element. Interference between the two second-order microring stages gave rise to a fourth-order filter response with flat-top passband and a bandwidth of 100 GHz. The result demonstrates the feasibility of realizing advanced integrated optics filters based on parallel cascades of high-order microring networks.