Stat1 Is Induced and Activated by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia Cells

Giannı̀, Maurizio; Terao, Mineko; Fortino, Ida; LiCalzi, Marco; Viggiano, Vincenzo; Barbui, Tiziano; Rambaldi, Alessandro; Garattini, Enrico

doi:10.1182/blood.v89.3.1001

Cited by 106 publications

(33 citation statements)

References 34 publications

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“…Among at least seven members, STAT1 has been reported to play essential roles in myeloid differentiation. STAT1 activation was first identified in ATRA-induced myeloid differentiation of various leukemia cell lines [32]. In addition, STAT1 was also reported to be activated by Bryostatin 1 to mediate the differentiation of chronic lymhocytic leukemia cells (CLL).…”

Section: Discussionmentioning

confidence: 99%

MEK/ERK Dependent Activation of STAT1 Mediates Dasatinib-Induced Differentiation of Acute Myeloid Leukemia

et al. 2013

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Dasatinib (BMS-354825) is a FDA-approved multitargeted kinase inhibitor of BCR/ABL and Src kinases. It is now used in the treatment of chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapies, including imatinib. Here we report a novel effect of dasatinib on inducing the differentiation of acute myeloid leukemia (AML) cells through MEK/ERK-dependent activation of signal transducer and activator of transcription 1 (STAT1). We found that dasatinib could induce the differentiation of AML cells as demonstrated by the expression of differentiation marker CD11b, G0/G1 phase arrest and decreased ratio of nucleus to cytoplasm. Of note, dasatinib induced robust phosphorylation of STAT1 both at Tyr701 and Ser727 as well as the redistribution of STAT1 from the cytoplasm to the nucleus, thus leading to the transcription of STAT1-targeted genes. Knocking down STAT1 expression by shRNA significantly attenuated dasatinib-induced differentiation, indicating an important role of STAT1 in myeloid maturation. We further found that dasatinib-induced activation of STAT1 was regulated by the MEK/ERK kinases. The phosporylation of MEK and ERK occurred rapidly upon dasatinib treatment and increased progressively as differentiation was induced. MEK inhibitors PD98059 and U0216 not only inhibited the phosphorylation of STAT1, but also abrogated dasatinib-induced myeloid differentiation, suggesting that MEK/ERK dependent phosphorylation of STAT1 might be indispensable for the differentiating effect of dasatinib in AML cells. Taken together, our study suggests that STAT1 is an important mediator in dasatinib-induced differentiation of AML cells, whose activation requires the activation of MEK/ERK cascades.

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Section: Discussionmentioning

confidence: 99%

MEK/ERK Dependent Activation of STAT1 Mediates Dasatinib-Induced Differentiation of Acute Myeloid Leukemia

et al. 2013

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“…The retinoic acid-mediated accumulation of ISG15 and its conjugates occurs in retinoic acid-sensitive leukemic cells but not in retinoic acid-resistant cells and the pattern of accumulated ISG15 conjugates is similar to that observed by the exposure to type I IFNs. In addition, several of the type I IFNinduced proteins, such as IRF-1 and (2′-5′) oligoadenylate synthetase, are induced by retinoic acid [70][71][72]. Treatment with retinoic acid also leads to an increased secretion of type I IFNs into culture media.…”

Section: Control Of Isg15 Inductionmentioning

confidence: 99%

ISG15 and immune diseases

Jeon

Yoo

Chung

2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

147

170

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ISG15, the product of interferon (IFN)-stimulated gene 15, is the first identified ubiquitin-like protein, consisting of two ubiquitin-like domains. ISG15 is synthesized as a precursor in certain mammals and, therefore, needs to be processed to expose the C-terminal glycine residue before conjugation to target proteins. A set of three-step cascade enzymes, an E1 enzyme (UBE1L), an E2 enzyme (UbcH8), and one of several E3 ligases (e.g., EFP and HERC5), catalyzes ISG15 conjugation (ISGylation) of a specific protein. These enzymes are unique among the cascade enzymes for ubiquitin and other ubiquitin-like proteins in that all of them are induced by type I IFNs or other stimuli, such as exposure to viruses and lipopolysaccharide. Mass spectrometric analysis has led to the identification of several hundreds of candidate proteins that can be conjugated by ISG15. Some of them are type I IFN-induced proteins, such as PKR and RIG-I, and some are the key regulators that are involved in IFN signaling, such as JAK1 and STAT1, implicating the role of ISG15 and its conjugates in type I IFN-mediated innate immune responses. However, relatively little is known about the functional significance of ISG15 induction due to the lack of information on the consequences of its conjugation to target proteins. Here, we describe the recent progress made in exploring the biological function of ISG15 and its reversible modification of target proteins and thus in their implication in immune diseases.

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“…Monocytic cells are known to be infected during measles and have been suggested to play an important role in the spread of infection within the body (36,37). U937 cells were chosen because they are one of the few lines that have been used independently to study both retinoid and MeV biology (18,37). U937 cells have also been used to demonstrate that retinoids can influence elements of the type I IFN response (18).…”

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confidence: 99%

“…U937 cells were chosen because they are one of the few lines that have been used independently to study both retinoid and MeV biology (18,37). U937 cells have also been used to demonstrate that retinoids can influence elements of the type I IFN response (18).…”

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confidence: 99%

Retinoids inhibit measles virus through a type I IFN‐dependent bystander effect

et al. 2009

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Measles-associated mortality can be decreased in response to treatment with vitamin A. Our goal was to understand the mechanism by which vitamin A and other retinoids reduce measles virus (MeV) replication in vitro. MeV is known to inhibit type I interferon (IFN) signaling, and retinoids are increasingly implicated in modulating innate immunity. Type I IFN blocking antibodies abrogated the inhibitory effects of all-trans retinoic acid (ATRA) on MeV replication (EC(50) of ATRA: 3.17 x 10(-8) M). IFN-stimulated genes (ISGs) are up-regulated by ATRA in MeV-infected U937 cell cultures starting at 12 h and reaching a plateau at 24 h postinfection when compared to either treatment or infection alone. We found that this increased gene expression occurs in uninfected cells by using a transwell system where the uninfected cells were separated from infected cells by a membrane with 0.02-muM pores. Uninfected bystander cells from the ATRA-treated transwells did not support substantial viral replication when subsequently infected with MeV. In the absence of ATRA, the cells from the uninfected chamber did not up-regulate ISG expression and were not protected from subsequent challenge with virus. These results demonstrate that retinoids inhibit MeV replication by up-regulating elements of the innate immune response in uninfected bystander cells, making them refractory to productive infection during subsequent rounds of viral replication.

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Stat1 Is Induced and Activated by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia Cells

Cited by 106 publications

References 34 publications

MEK/ERK Dependent Activation of STAT1 Mediates Dasatinib-Induced Differentiation of Acute Myeloid Leukemia

MEK/ERK Dependent Activation of STAT1 Mediates Dasatinib-Induced Differentiation of Acute Myeloid Leukemia

ISG15 and immune diseases

Retinoids inhibit measles virus through a type I IFN‐dependent bystander effect

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