RESUMO
Prolonged exit from quiescence by hematopoietic stem cells (HSCs) progressively impairs their homeostasis in the bone marrow through an unidentified mechanism. We show that Rb proteins, which are major enforcers of quiescence, maintain HSC homeostasis by positively regulating thrombopoietin (Tpo)-mediated Jak2 signaling. Rb family protein inactivation triggers the progressive E2f-mediated transactivation of Socs3, a potent inhibitor of Jak2 signaling, in cycling HSCs. Aberrant activation of Socs3 impairs Tpo signaling and leads to impaired HSC homeostasis. Therefore, Rb proteins act as a central hub of quiescence and homeostasis by coordinating the regulation of both cell cycle and Jak2 signaling in HSCs.
Assuntos
Células-Tronco Hematopoéticas/metabolismo , Homeostase/genética , Proteína do Retinoblastoma/genética , Proteína p107 Retinoblastoma-Like/genética , Proteína p130 Retinoblastoma-Like/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Animais , Ciclo Celular/genética , Divisão Celular/genética , Proliferação de Células/genética , Fatores de Transcrição E2F/genética , Fatores de Transcrição E2F/metabolismo , Perfilação da Expressão Gênica/métodos , Immunoblotting , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Interferência de RNA , Proteína do Retinoblastoma/metabolismo , Proteína p107 Retinoblastoma-Like/metabolismo , Proteína p130 Retinoblastoma-Like/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Trombopoetina/farmacologia , Ativação TranscricionalRESUMO
It has been suggested that alterations of cell cycle genes probably contribute to the pathogenesis of endemic Burkitt's lymphoma (BL) in addition to c-MYC translocation. Mutations disrupting the normal nuclear localization signal of the retinoblastoma-related gene Rb2/p130 have been documented in BL cell lines and primary tumors from endemic areas. The aim of this study was to investigate the involvement of Rb2/p130 gene in the pathogenesis of sporadic BL in Brazil. DNA samples from 26 pediatric BL tumors and two healthy blood donors were screened by PCR amplification followed by single strand conformation polymorphism analysis of exons 19 and 20 (B domain) and exons 21 and 22 (C-terminus), where most of the point mutations in the Rb2/p130 gene were identified. No abnormal band shifts were present in the samples analyzed. We concluded that mutations in exons 19-22 of the Rb2/p130 are unlikely to be involved directly in the pathogenesis of sporadic Brazilian BL.