RTP801 is a novel retinoic acid–responsive gene associated with myeloid differentiation

Gery, Sigal; Park, Dorothy J.; Vuong, Peter T.; Virk, Renu K.; Müller, Claudia I.; Hofmann, Werner; Koeffler, H. Phillip

doi:10.1016/j.exphem.2007.01.049

Cited by 30 publications

(30 citation statements)

References 27 publications

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“…42 It has further been shown that this effect of ATRA is mediated through the stress response gene RTP801, an early RA target gene in myeloid cells, which acts as a negative regulator of the mTOR pathway. 42,43 Further, autophagic death of acute lymphoblastic lymphoma cells treated with dexamethasone was recently shown to be dependent on the PML protein, which is known to represent an inhibitor of mTOR activity. 44,45 Thus, mTOR-regulated autophagy may play a general role in development and treatment of leukemia.…”

Section: Discussionmentioning

confidence: 99%

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Isakson

Bjørås

Bøe

et al. 2010

Blood

247

231

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IntroductionThe promyelocytic leukemia/retinoic acid receptor alpha (PML/ RARA) oncoprotein, which is expressed by the acute promyelocytic leukemia (APL)-specific t(15;17) chromosomal translocation, is known to inhibit granulocyte development at the promyelocytic stage of differentiation and to promote malignant transformation of hematopoietic progenitor cells mainly by acting as a repressor of gene expression. [1][2][3] All-trans retinoic acid (ATRA), the first of 2 drugs that was found to cause disease regression specifically in APL patients, interacts with the ligand binding domain present on the RARA moiety of the chimeric oncoprotein and causes both its transcriptional activation, as well as its proteolytic degradation, an effect that phenotypically leads to granulocyte differentiation of APL cells. 3,4 In later years, arsenic trioxide (ATO) also has been shown to be remarkably effective as an agent that cures APL. 4 Compared with ATRA, this drug appears to have a more limited capacity to induce differentiation and is thought to induce disease regression mainly by causing proteolytic degradation of PML/RARA. 4,5 The mechanism by which ATO causes PML/RARA proteolysis was recently shown to involve PML small ubiquitin-like modifier (SUMO)-ylation and subsequent poly-ubiquitination and proteolytic degradation of PML and PML/RARA by a protein called RNF4. 6,7 The ability of ATRA and ATO to activate disease regression through distinct molecular mechanisms that lead to PML/RARA degradation is further underscored by recent studies in which the authors showed a synergy effect of these 2 drugs both in their ability to induce clinical remission of APL patients, 8,9 as well as their capacity to cause PML/RARA degradation. 5 Thus, the ability of ATRA and ATO to activate PML/RARA degradation appears to represent a critical parameter for successful APL treatment.Two major routes for degradation of intracellular proteins exist: the ubiquitin-proteasome system (UPS) and the autophagylysosome pathway. The UPS generally is used for degradation of short-lived soluble proteins and misfolded proteins after their labeling with poly-ubiquitin chains. However, misfolded proteins that accumulate to form larger aggregates generally are poor substrates for the UPS. 10 Macro-autophagy, hereafter referred to as autophagy, involves the turnover of cytoplasmic macromolecules, protein aggregates, and defective organelles by their sequestration by double-layered membranes that form autophagosomes, which eventually fuse with lysosomes in which the sequestered contents are degraded. 11 Mice and flies lacking essential autophagy genes are characterized by increased tumorigenesis 12-14 and encompass neurodegenerative phenotypes, [15][16][17] indicating that autophagy is an important tumor-suppressive and neuroprotective mechanism.The authors of previous studies have implicated an important role of the UPS in therapy-induced degradation of PML/RARA. This role is evident from experiments showing that ATRA and ATO-induced PML/RARA degradation is b...

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Section: Discussionmentioning

confidence: 99%

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Isakson

Bjørås

Bøe

et al. 2010

Blood

247

231

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“…RTP801 is a negative regulator of the mTOR pathway. 37 It is unlikely that MS-275 induced differentiation of AML cells and inhibited mTOR signaling through RTP801. MS-275 inhibited both Akt and mTOR ( Figure 1); however, RTP801 was shown to inhibit mTOR but not Akt.…”

Section: Discussionmentioning

confidence: 99%

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

et al. 2008

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This study found that MS-275, a novel synthetic benzamide histone deacetylase inhibitor (HDACI), blocked Akt/mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) HL60 and acute promyelocytic leukemia (APL) NB4 cells, as assessed by decreased levels of the phosphorylated (p)-Akt, p-p70 ribosomal S6 kinase (p70S6K) and p-S6K by western blot analysis. Interestingly, further inactivation of mTOR by rapamycin analog RAD001 (everolimus) significantly enhanced MS-275-mediated growth inhibition and apoptosis of these cells in parallel with enhanced upregulation of p27 kip1 and downregulation of c-Myc. In addition, RAD001 potentiated the ability of MS-275 to induce differentiation of HL60 and NB4 cells, as measured by the expression of CD11b cell surface antigens, as well as reduction of nitroblue tetrazolium. Importantly, RAD001 potentiated the ability of MS-275 to induce the expression of the myeloid differentiation-related transcription factor, CCAAT enhancer-binding protein-e, in these cells in association with enhanced acetylation of histone H3 on its promoter. Furthermore, RAD001 (5 mg/kg) significantly enhanced the effects of MS-275 (10 mg/kg) to inhibit proliferation of HL60 tumor xenografts in nude mice without adverse effects. Taken together, concomitant administration of an HDACI and an mTOR inhibitor may be a promising treatment strategy for the individuals with a subset of human leukemia.

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“…In contrast, the cellular compartment in which REDD1 resides for mTORC1 regulation is likely to be a tritoninsoluble membrane fraction which contains the majority of cellular Rheb, the target of REDD1-TSC1/2 activity (16). Although the specific mechanism of REDD1 function in the mitochondria awaits further studies, REDD1 has been reported to interact with mitochondrial proteins in vitro (26), suggesting the possibility of a direct effect of REDD1 on electron transport.…”

Section: Consequently Redd1mentioning

confidence: 99%

Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis

Horak

Crawford²,

Vadysirisack³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

170

161

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The HIF family of hypoxia-inducible transcription factors are key mediators of the physiologic response to hypoxia, whose dysregulation promotes tumorigenesis. One important HIF-1 effector is the REDD1 protein, which is induced by HIF-1 and which functions as an essential regulator of TOR complex 1 (TORC1) activity in Drosophila and mammalian cells. Here we demonstrate a negative feedback loop for regulation of HIF-1 by REDD1, which plays a key role in tumor suppression. Genetic loss of REDD1 dramatically increases HIF-1 levels and HIF-regulated target gene expression in vitro and confers tumorigenicity in vivo. Increased HIF-1 in REDD1 −/− cells induces a shift to glycolytic metabolism and provides a growth advantage under hypoxic conditions, and HIF-1 knockdown abrogates this advantage and suppresses tumorigenesis. Surprisingly, however, HIF-1 up-regulation in REDD1−/− cells is largely independent of mTORC1 activity. Instead, loss of REDD1 induces HIF-1 stabilization and tumorigenesis through a reactive oxygen species (ROS) -dependent mechanism. REDD1 −/− cells demonstrate a substantial elevation of mitochondrial ROS, and antioxidant treatment is sufficient to normalize HIF-1 levels and inhibit REDD1-dependent tumor formation. REDD1 likely functions as a direct regulator of mitochondrial metabolism, as endogenous REDD1 localizes to the mitochondria, and this localization is required for REDD1 to reduce ROS production. Finally, human primary breast cancers that have silenced REDD1 exhibit evidence of HIF activation. Together, these findings uncover a specific genetic mechanism for HIF induction through loss of REDD1. Furthermore, they define REDD1 as a key metabolic regulator that suppresses tumorigenesis through distinct effects on mTORC1 activity and mitochondrial function.hypoxia | mTOR | mitochondria | breast cancer | tuberous sclerosis C ontrol of cellular metabolism plays an important role in human tumorigenesis. Nascent tumor cells must survive a variety of environmental stresses, including hypoxia and energy stress, to allow tumor progression (1, 2). A key mediator of these metabolic adaptations is the hypoxia-inducible factor HIF. HIF is a heterodimeric transcription factor whose activity is induced in response to hypoxia and which regulates genes that mediate a variety of hypoxia-adaptive functions including the shift to glycolytic metabolism, enhancement of angiogenesis, and suppression of oxidative phosphorylation (3-5). The HIF family includes three HIFα subunits (HIF-1α, HIF-2α, and HIF-3α) and a common HIF-1β subunit (also known as ARNT). The key role of HIF in human tumorigenesis is underscored by von Hippel-Lindau (VHL) tumor suppressor syndrome, which results from germline mutations in VHL, a gene encoding a subunit of a ubiquitin ligase complex which targets HIFα subunits for oxygen-dependent degradation (6). Other pathways may contribute to HIF dysregulation in different cancer settings, as recent work has demonstrated an important role for aberrant HIF up-regulation in promoting tumorigenes...

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RTP801 is a novel retinoic acid–responsive gene associated with myeloid differentiation

Cited by 30 publications

References 27 publications

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein

Blockade of mTOR signaling potentiates the ability of histone deacetylase inhibitor to induce growth arrest and differentiation of acute myelogenous leukemia cells

Negative feedback control of HIF-1 through REDD1-regulated ROS suppresses tumorigenesis

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