RESUMEN
Epithelial to mesenchymal transition (EMT) is a physiological process during development where epithelial cells transform to acquire mesenchymal characteristics, which allows them to migrate and colonize secondary tissues. Many cellular signaling pathways and master transcriptional factors exert a myriad of controls to fine tune this vital process to meet various developmental and physiological needs. Adding to the complexity of this network are post-transcriptional and post-translational regulations. Among them, alternative splicing has been shown to play important roles to drive EMT-associated phenotypic changes, including actin cytoskeleton remodeling, cell-cell junction changes, cell motility and invasiveness. In advanced cancers, transforming growth factor-ß (TGF-ß) is a major inducer of EMT and is associated with tumor cell metastasis, cancer stem cell self-renewal, and drug resistance. This review aims to provide an overview of recent discoveries regarding alternative splicing events and the involvement of splicing factors in the EMT and TGF-ß signaling. It will emphasize the importance of various splicing factors involved in EMT and explore their regulatory mechanisms.
Asunto(s)
Empalme Alternativo , Transición Epitelial-Mesenquimal , Neoplasias , Transducción de Señal , Factor de Crecimiento Transformador beta , Humanos , Transición Epitelial-Mesenquimal/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/genética , Neoplasias/genética , Neoplasias/patología , Neoplasias/metabolismo , Animales , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión GénicaRESUMEN
In this issue of Cell Chemical Biology, Liu et al.1 report the identification of Q29, a synthetic diterpenoid that blocks covalent cholesterol modification of smoothened (SMO) and inhibits hedgehog signaling. Q29 is capable of suppressing tumor cell growth, both in vitro and in vivo, and overcoming resistance to SMO inhibitors.
Asunto(s)
Colesterol , Diterpenos , Resistencia a Antineoplásicos , Proteínas Hedgehog , Receptor Smoothened , Humanos , Receptor Smoothened/antagonistas & inhibidores , Receptor Smoothened/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Colesterol/metabolismo , Colesterol/química , Diterpenos/farmacología , Diterpenos/química , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Animales , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Antineoplásicos/farmacología , Antineoplásicos/química , Transducción de Señal/efectos de los fármacosRESUMEN
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and multiple vital organs, but the immunological pathogenesis of SSc remains unclear. We show here that miR-19b promotes Th9 cells that exacerbate SSc. Specifically, miR-19b and interleukin (IL)-9 increase in CD4+ T cells in experimental SSc in mice induced with bleomycin. Inhibiting miR-19b reduces Th9 cells and ameliorates the disease. Mechanistically, transforming growth factor beta (TGF-ß) plus IL-4 activates pSmad3-Ser213 and TRAF6-K63 ubiquitination by suppressing NLRC3. Activated TRAF6 sequentially promotes TGF-ß-activated kinase 1 (TAK1) and nuclear factor κB (NF-κB) p65 phosphorylation, leading to the upregulation of miR-19b. Notably, miR-19b activated Il9 gene expression by directly suppressing atypical E2F family member E2f8. In patients with SSc, higher levels of IL9 and MIR-19B correlate with worse disease progression. Our findings reveal miR-19b as a key factor in Th9 cell-mediated SSc pathogenesis and should have clinical implications for patients with SSc.