RESUMEN
When proteostasis is disrupted by stresses such as heat shock, the heat stress response will be stimulated, leading to up-regulation of molecular chaperones by transcriptional activation and mRNA stabilization for restoring proteostasis. Although the mechanisms for their transcriptional activation have been clearly defined, how chaperone mRNAs are stabilized remains largely unknown. Starting by exploring the coupling between the apparently unrelated RNA degradation and protein quality control (PQC) systems, we show that the Dis3 ribonuclease, catalytic subunit of the RNA exosome required for RNA degradation, suppresses PQC activity in unstressed cells by degrading mRNAs encoding the Hsp70 cofactors Sis1, Ydj1 and Fes1, as well as some other chaperones or PQC factors, thereby limiting their protein expression. Dis3 is stabilized through its binding to Sis1 and the Hsp70s Ssa1/2. Upon heat stress, loss of Sis1 and Ssa1/2 availability triggers Dis3 ubiquitination and degradation, leading to stabilization of those chaperone mRNAs originally targeted by Dis3. We further demonstrate that polyQ-expanded huntingtin delays Dis3 degradation during heat stress and thus hinders chaperone mRNA stabilization. Our findings not only reveal a post-transcriptional negative feedback loop for maintaining proteostasis, but also uncover a mechanism that contributes to the impaired heat stress response in Huntington's disease.
Asunto(s)
Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Exosomas/genética , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Procesamiento Proteico-Postraduccional/genética , Retroalimentación Fisiológica , Proteínas del Choque Térmico HSP40/genética , Proteínas HSP70 de Choque Térmico/genética , Respuesta al Choque Térmico/genética , Humanos , Enfermedad de Huntington/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos/genética , Proteostasis/genética , Estabilidad del ARN/genética , ARN Mensajero/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T lymphoblastic leukemia (T-ALL) identified in 2009, due to its unique immunophenotypic and genomic profile. The outcome of patients was poor in earlier studies, and they were prone to have induction failure, with more frequent relapse/refractory disease. Recent advances had been made in discoveries of genetic aberrations and molecular pathogenesis of ETP-ALL. However, the diagnosis and management of ETP-ALL is still challenging. There are limited choices of novel therapies so far. In this review article, it highlighted the diagnostic issue of ETP-ALL, pitfall in diagnosis, and strategy of accurate diagnosis. The review also summarized current understanding of molecular mechanism of leukemogenesis. The emerging role of risk-adapted therapy and allogenic stem cell transplant in optimizing the outcome of patients with ETP-ALL was discussed. Finally, some potential novel therapies were proposed based on the current understanding of molecular pathogenesis.
RESUMEN
Acute lymphoblastic leukaemia (ALL) is an aggressive haematolymphoid malignancy. The prognosis of ALL is excellent in paediatric population, however the outcome of relapse/refractory disease is dismal. Adult ALL has less favourable prognosis and relapse/refractory disease is not uncommonly encountered. Bortezomib is the first generation proteasome inhibitor licensed to treat plasma cell myeloma and mantle cell lymphoma with favourable side effect profile. Efficacy of bortezomib had been proven in other solid tumors. Clinical studies showed promising response for proteasome inhibitors in treating relapse/refractory ALL. Thus, proteasome inhibitors are attractive alternative agents for research in treating ALL. In the review article, we will introduce different proteasome inhibitors and their difference in pharmacological properties. Moreover, the mechanism of action of proteasome inhibitors on ALL will be highlighted. Finally, results of various clinical studies on proteasome inhibitors in both paediatric and adult ALL will be discussed. This review article provides the insights on the use of proteasome inhibitors in treating ALL with a summary of mechanism of action in ALL which facilitates future research on its use to improve the outcome of ALL.