ABSTRACT
Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBL.
Subject(s)
Leukemia-Lymphoma, Adult T-Cell , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Humans , Janus Kinases/metabolism , Signal Transduction , Suppressor of Cytokine Signaling 3 Protein/genetics , Suppressor of Cytokine Signaling 3 Protein/metabolism , STAT Transcription Factors/metabolism , STAT3 Transcription Factor/metabolism , Suppressor of Cytokine Signaling Proteins/metabolism , T-Lymphocytes/metabolismABSTRACT
Human PrimPol is a primase belonging to the AEP superfamily with the unique ability to synthesize DNA primers de novo, and a non-processive DNA polymerase able to bypass certain DNA lesions. PrimPol facilitates both mitochondrial and nuclear replication fork progression either acting as a conventional TLS polymerase, or repriming downstream of blocking lesions. In vivo assays have shown that PrimPol is rapidly recruited to sites of DNA damage by interaction with the human replication protein A (RPA). In agreement with previous findings, we show here that the higher affinity of RPA for ssDNA inhibits PrimPol activities in short ssDNA templates. In contrast, once the amount of ssDNA increases up to a length in which both proteins can simultaneously bind ssDNA, as expected during replicative stress conditions, PrimPol and RPA functionally interact, and their binding capacities are mutually enhanced. When using M13 ssDNA as template, RPA stimulated both the primase and polymerase activities of PrimPol, either alone or in synergy with Polε. These new findings supports the existence of a functional PrimPol/RPA association that allows repriming at the exposed ssDNA regions formed in the leading strand upon replicase stalling.
Subject(s)
DNA Primase/metabolism , DNA-Directed DNA Polymerase/metabolism , Multifunctional Enzymes/metabolism , Replication Protein A/metabolism , DNA Replication , DNA, Single-Stranded/genetics , DNA, Single-Stranded/metabolism , Enzyme Activation , Humans , Protein Binding , Substrate Specificity , Templates, GeneticABSTRACT
Brindar al estudiante tanto de pregrado como de postgradoun medio de enseñanza novedoso, que le permita suplir la falta de literatura actualizada sobre el tema, motivarlos en el aprendizaje de la hemostasia y los medicamentos utilizados para regularla de manera adecuada, abordando en esta primera versión los medicamentos antiagragantes plaquetarios y anticoagulantes. También permite aplicar sus conocimientos y adiestrarse en el uso de la informática médica. Para realizar esta página WEB empleamos una PC, que nos permitió utilizar el MICROSOFT WORD del OFFICE 2000, ue cuenta con el asistente para confección de páginas WEB y utilizamos el lenguaje HTML(AU)
