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1.
Mol Cell ; 53(3): 407-19, 2014 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-24412064

RESUMEN

Retinoic acid (RA)-inducible gene I (RIG-I) is highly upregulated and functionally implicated in the RA-induced maturation of acute myeloid leukemia (AML) blasts. However, the underlying mechanism and the biological relevance of RIG-I expression to the maintenance of leukemogenic potential are poorly understood. Here, we show that RIG-I, without priming by foreign RNA, inhibits the Src-facilitated activation of AKT-mTOR in AML cells. Moreover, in a group of primary human AML blasts, RIG-I reduction renders the Src family kinases hyperactive in promoting AKT activation. Mechanistically, a PxxP motif in RIG-I, upon the N-terminal CARDs' association with the Src SH1 domain, competes with the AKT PxxP motif for recognizing the Src SH3 domain. In accordance, mutating PxxP motif prevents Rig-I from inhibiting AKT activation, cytokine-stimulated myeloid progenitor proliferation, and in vivo repopulating capacity of leukemia cells. Collectively, our data suggest an antileukemia activity of RIG-I via competitively inhibiting Src/AKT association.


Asunto(s)
ARN Helicasas DEAD-box/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Proteínas Proto-Oncogénicas pp60(c-src)/fisiología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/fisiología , Secuencia de Aminoácidos , Línea Celular Tumoral , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/química , ARN Helicasas DEAD-box/genética , Activación Enzimática , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Modelos Genéticos , Datos de Secuencia Molecular , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Receptores Inmunológicos , Alineación de Secuencia , Análisis de Secuencia de Proteína , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/fisiología , Regulación hacia Arriba
2.
Proc Natl Acad Sci U S A ; 108(5): 1897-902, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21224412

RESUMEN

RA-inducible gene I (RIG-I/DDX58) has been shown to activate IFN-ß promoter stimulator 1 (IPS-1) on recognizing cytoplasmic viral RNAs. It is unclear how RIG-I functions within the IFN and/or RA signaling process in acute myeloid leukemia (AML) cells, however, where obvious RIG-I induction is observed. Here, we show that the RIG-I induction functionally contributes to IFN-α plus RA-triggered growth inhibition of AML cells. Interestingly, although RIG-I induction itself is under the regulation of STAT1, a major IFN intracellular signal mediator, under circumstances in which it does not stimulate IPS-1, it conversely augments STAT1 activation to induce IFN-stimulatory gene expression and inhibit leukemia cell proliferation. Thus, our results unveil a previously undescribed RIG-I activity in regulating the cellular proliferation of leukemia cells via STAT1, which is independent of its classic role of sensing viral invasion to trigger type I IFN transcription.


Asunto(s)
Proliferación Celular , ARN Helicasas DEAD-box/genética , Leucemia/patología , Factor de Transcripción STAT1/metabolismo , Proteína 58 DEAD Box , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Receptores Inmunológicos , Tretinoina/farmacología , Células U937
3.
Proc Natl Acad Sci U S A ; 105(30): 10553-8, 2008 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-18650396

RESUMEN

RIG-I has been implicated in innate immunity by sensing intracellular viral RNAs and inducing type I IFN production. However, we have found a significant RIG-I induction in a biological setting without active viral infection-namely, during RA-induced terminal granulocytic differentiation of acute myeloid leukemias. Here, we present evidence that a significant Rig-I induction also occurs during normal myelopoiesis and that the disruption of the Rig-I gene in mice leads to the development of a progressive myeloproliferative disorder. The initiation of progressive myeloproliferative disorder is mainly due to an intrinsic defect of Rig-I(-/-) myeloid cells, which are characterized by a reduced expression of IFN consensus sequence binding protein, a major regulator of myeloid differentiation. Thus, our study reveals a critical regulatory role of Rig-I in modulating the generation and differentiation of granulocytes.


Asunto(s)
ARN Helicasas DEAD-box/fisiología , Regulación de la Expresión Génica , Granulocitos/citología , Receptores de Ácido Retinoico/fisiología , Animales , Diferenciación Celular , Proliferación Celular , Proteína 58 DEAD Box , Exones , Granulocitos/metabolismo , Células Madre Hematopoyéticas/citología , Humanos , Inmunidad Innata , Ratones , Ratones Noqueados , Ratones Transgénicos , Células Mieloides/citología , Trastornos Mieloproliferativos/metabolismo
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