RESUMEN
A tricyclic phosphine has been generated that has a rigid molecular backbone with the P atoms exclusively bound to C(sp2 ) atoms as well as a very large Tolman angle and buried volume. It is an interesting new ligand in coordination chemistry (Au, Pd complexes) and shows unusual insertion reactions into its endocyclic P-C bonds facilitated by its inherent molecular strain.
RESUMEN
Lymphangioleiomyomatosis (LAM) is a rare progressive disease, characterized by mutations in the tuberous sclerosis complex genes (TSC1 or TSC2) and hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1). Here, we report that E26 transformation-specific (ETS) variant transcription factor 2 (ETV2) is a critical regulator of Tsc2-deficient cell survival. ETV2 nuclear localization in Tsc2-deficient cells is mTORC1-independent and is enhanced by spleen tyrosine kinase (Syk) inhibition. In the nucleus, ETV2 transcriptionally regulates poly(ADP-ribose) polymerase 1 binding protein (PARPBP) mRNA and protein expression, partially reversing the observed down-regulation of PARPBP expression induced by mTORC1 blockade during treatment with both Syk and mTORC1 inhibitors. In addition, silencing Etv2 or Parpbp in Tsc2-deficient cells induced ER stress and increased cell death in vitro and in vivo. We also found ETV2 expression in human cells with loss of heterozygosity for TSC2, lending support to the translational relevance of our findings. In conclusion, we report a novel ETV2 signaling axis unique to Syk inhibition that promotes a cytocidal response in Tsc2-deficient cells and therefore maybe a potential alternative therapeutic target in LAM.
Asunto(s)
Linfangioleiomiomatosis , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Proteínas de Unión al ADN/genética , Estrés del Retículo Endoplásmico , Humanos , Linfangioleiomiomatosis/tratamiento farmacológico , Linfangioleiomiomatosis/genética , Linfangioleiomiomatosis/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Factores de Transcripción/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Lung allograft rejection results in the accumulation of low-molecular weight hyaluronic acid (LMW-HA), which further propagates inflammation and tissue injury. We have previously shown that therapeutic lymphangiogenesis in a murine model of lung allograft rejection reduced tissue LMW-HA and was associated with improved transplant outcomes. Herein, we investigated the use of 4-Methylumbelliferone (4MU), a known inhibitor of HA synthesis, to alleviate acute allograft rejection in a murine model of lung transplantation. We found that treating mice with 4MU from days 20 to 30 after transplant was sufficient to significantly improve outcomes, characterized by a reduction in T cell-mediated lung inflammation and LMW-HA content and in improved pathology scores. In vitro, 4MU directly attenuated activation, proliferation, and differentiation of naive CD4+ T cells into Th1 cells. As 4MU has already been demonstrated to be safe for human use, we believe examining 4MU for the treatment of acute lung allograft rejection may be of clinical significance.