Asunto(s)
Médula Ósea/patología , Factor 88 de Diferenciación Mieloide/análisis , Células Plasmáticas/patología , Reacción en Cadena de la Polimerasa/métodos , Macroglobulinemia de Waldenström/patología , Anciano , Biopsia , Diferenciación Celular , Femenino , Humanos , Linfoma/química , Linfoma/diagnóstico , Linfoma/patología , Masculino , Persona de Mediana Edad , Factor 88 de Diferenciación Mieloide/genética , Macroglobulinemia de Waldenström/diagnósticoAsunto(s)
Antineoplásicos/uso terapéutico , Linfoma Intraocular/tratamiento farmacológico , Talidomida/análogos & derivados , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Biopsia , Femenino , Humanos , Linfoma Intraocular/diagnóstico , Retratamiento , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/farmacocinética , Talidomida/uso terapéutico , Resultado del TratamientoAsunto(s)
Factores Inmunológicos/uso terapéutico , Neoplasias Meníngeas/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Lenalidomida/administración & dosificación , Masculino , Neoplasias Meníngeas/diagnóstico , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Talidomida/administración & dosificación , Talidomida/uso terapéutico , Resultado del TratamientoAsunto(s)
Artritis/inducido químicamente , Enfermedades Autoinmunes/inducido químicamente , Eritema Nudoso/inducido químicamente , Factores Inmunológicos/efectos adversos , Linfadenopatía/inducido químicamente , Nefrosis Lipoidea/tratamiento farmacológico , Rituximab/efectos adversos , Articulación del Tobillo , Artritis/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Disnea/inducido químicamente , Eritema Nudoso/tratamiento farmacológico , Femenino , Glucocorticoides/uso terapéutico , Humanos , Linfadenopatía/diagnóstico por imagen , Linfadenopatía/tratamiento farmacológico , Depleción Linfocítica/métodos , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Nefrosis Lipoidea/complicaciones , Síndrome , Tomografía Computarizada por Rayos XRESUMEN
P27 Kip1 (p27) can prevent cell proliferation by inactivating cyclin-dependent kinases. This function is impaired upon phosphorylation of p27 at tyrosine residue 88. We observed that FLT3 and FLT3-ITD can directly bind and selectively phosphorylate p27 on this residue. Inhibition of FLT3-ITD in cell lines strongly reduced p27 tyrosine 88 phosphorylation and resulted in increased p27 levels and cell cycle arrest. Subsequent analysis revealed the presence of tyrosine 88 phosphorylated p27 in primary patient samples. Inhibition of FLT3 kinase activity with AC220 significantly reduced p27 tyrosine 88 phosphorylation in cells isolated from FLT3 wild type expressing acute myeloid leukemia (AML) patients. In FLT3-ITD positive AML patients, p27 tyrosine 88 phosphorylation was reduced in 5 out of 9 subjects, but, surprisingly, was increased in 4 patients. This indicated that other tyrosine kinases such as Src family kinases might contribute to p27 tyrosine 88 phosphorylation in FLT3-ITD positive AML cells. In fact, incubation with the Src family kinase inhibitor dasatinib could decrease p27 tyrosine 88 phosphorylation in these patient samples, indicating that p27 phosphorylated on tyrosine 88 may be a therapeutic marker for the treatment of AML patients with tyrosine kinase inhibitors.
Asunto(s)
Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Leucemia Mieloide Aguda/metabolismo , Tirosina Quinasa 3 Similar a fms/metabolismo , Puntos de Control del Ciclo Celular , Humanos , Fosforilación , Inhibidores de Proteínas Quinasas/metabolismo , Secuencias Repetidas en Tándem , Células Tumorales Cultivadas , Tirosina/metabolismoRESUMEN
Extracellular mitogen signal transduction is initiated by ligand binding to specific receptors of target cells. This causes a cellular response that frequently triggers the activation of tyrosine kinases. Non-receptor kinases like Src and Lyn can directly phosphorylate the Cdk inhibitor protein p27 (Kip1) . Tyrosine phosphorylation can cause impaired Cdk-inhibitory activity and decreased stability of p27. In addition to these non-receptor tyrosine kinases, the receptor-associated tyrosine kinase Janus kinase 2 (JAK2) was recently identified to phosphorylate p27. JAK2 becomes activated through binding of various cytokines and growth factors to their corresponding receptors and can directly bind and selectively phosphorylate tyrosine residue 88 (Y88) of the Cdk inhibitor p27. This impairs Cdk inhibition by p27 and promotes its ubiquitin-dependent proteasomal degradation. Via this mechanism, JAK2 can link cytokine and growth factor initiated signal transduction to p27 regulation, whereas oncogenes like JAK2V617F or BCR-Abl can use this mechanism to inactivate the Cdk inhibitor.
Asunto(s)
Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Mitógenos/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , Humanos , Interfase , Janus Quinasa 2/metabolismo , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , Transducción de Señal , Tirosina/metabolismoRESUMEN
The Bcl-2 regulated apoptosis pathway is critical for the elimination of autoreactive lymphocytes, thereby precluding autoimmunity. T cells escaping this process can be kept in check by regulatory T (Treg) cells expressing the transcription and lineage commitment factor Foxp3. Despite the well-established role of Bcl-2 family proteins in shaping the immune system and their frequent deregulation in autoimmune pathologies, it is poorly understood how these proteins affect Treg cell development and function. Here we compared the relative expression of a panel of 40 apoptosis-associated genes in Treg vs. conventional CD4(+) T cells. Physiological significance of key-changes was validated using gene-modified mice lacking or overexpressing pro- or anti-apoptotic Bcl-2 family members. We define a key role for the Bim/Bcl-2 axis in Treg cell development, homeostasis and function but exclude a role for apoptosis induction in responder T cells as relevant suppression mechanism. Notably, only lack of the pro-apoptotic BH3-only protein Bim or Bcl-2 overexpression led to accumulation of Treg cells while loss of pro-apoptotic Bad, Bmf, Puma or Noxa had no effect. Remarkably, apoptosis resistant Treg cells showed reduced suppressive capacity in a model of T cell-driven colitis, posing a caveat for the use of such long-lived cells in possible therapeutic settings.