Expression of retinoic acid receptor–target genes during retinoic acid therapy for acute promyelocytic leukemia

Takitani, Kimitaka; Koh, Maki; Zhu, C L; Inoue, Akiko; Kuno, Tomoko; Tanoue, Hironori; Miyake, Munenori; Nakagawa, Toshimasa; Tamai, Hiroshi

doi:10.1038/sj.leu.2402818

Cited by 3 publications

(2 citation statements)

References 9 publications

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“…In addition, BTG1 stimulates the transcriptional activity of RAR (19), and RAR stimulates the c‐Jun promoter (21), suggesting the involvement of RAR in BTG1‐mediated c‐Jun expression. Indeed, although RARα expression was not altered, the expression of RARa well‐known downstream target CD38 (22) was increased by Ad‐BTG1 or decreased by Ad‐shBTG1 in liver (Fig. 8 B, C ).…”

Section: Resultsmentioning

confidence: 95%

A novel function of B‐cell translocation gene 1 ( BTG1 ) in the regulation of hepatic insulin sensitivity in mice via c‐Jun

Xiao

Deng

et al. 2015

FASEB j.

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Insulin resistance is one of the major factors contributing to metabolic diseases, but the underlying mechanisms are still poorly understood. As an important cofactor, B-cell translocation gene 1 (BTG1) is involved in many physiologic processes; however, the direct effect of BTG1 on insulin sensitivity has not been described. In our study, BTG1 overexpression or knockdown improved or impaired insulin signaling in vitro, respectively. In addition, adenovirus-mediated BTG1 overexpression improved insulin sensitivity in wild-type (WT) and insulin-resistant leptin-receptor mutated (db/db) mice. In addition, transgenic BTG1-overexpressing mice were resistant to high-carbohydrate diet-induced insulin resistance. Adenovirus-mediated BTG1 knockdown consistently impaired insulin sensitivity in WT and insulin-sensitive leucine-deprived mice. Moreover, hepatic BTG1 expression was increased by leucine deprivation via the mammalian target of rapamycin/ribosomal protein S6 kinase 1 pathway. Furthermore, c-Jun expression was up-regulated by BTG1, and adenovirus-mediated c-Jun knockdown blocked BTG1-improved insulin signaling and insulin sensitivity in vitro and in vivo. Finally, BTG1 promoted c-Jun expression via stimulating c-Jun and retinoic acid receptor activities. Taken together, these results identify a novel function for BTG1 in the regulation of hepatic insulin sensitivity and provide important insights into the nutritional regulation of BTG1 expression.- Xiao, F., Deng, J., Yu, J., Guo, Y., Chen, S., Guo, F. A novel function of B-cell translocation gene 1 (BTG1) in the regulation of hepatic insulin sensitivity in mice via c-Jun.

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Section: Resultsmentioning

confidence: 95%

A novel function of B‐cell translocation gene 1 ( BTG1 ) in the regulation of hepatic insulin sensitivity in mice via c‐Jun

Xiao

Deng

et al. 2015

FASEB j.

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“…ATRA activates the expression of a number of target genes involved in myeloid cell differentiation through interaction with nuclear receptor and transcription factor retinoic acid receptor α (RARα). 36,37 A scan of the region upstream of the miR-17-92 cluster revealed putative binding sites for CCAATT enhancer binding protein and transcription factor family member, C/EBPβ, a major ATRA target. The activation of C/EBPβ is an early event in the ATRA-induced differentiation response.…”

Section: Resultsmentioning

confidence: 99%

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

et al. 2016

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PHLPP2, a member of the PH-domain leucine-rich repeat protein phosphatase (PHLPP) family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little is known, however, regarding its regulation in hematological malignancies. We observed that PHLPP2 protein expression, but not its mRNA, was suppressed in late differentiation stage acute myeloid leukemia (AML) subtypes. MicroRNAs (miR or miRNAs) from the miR-17-92 cluster, oncomir-1, were shown to inhibit PHLPP2 expression and these miRNAs were highly expressed in AML cells that lacked PHLPP2 protein.Studies showed that miR-17-92 cluster regulation was, surprisingly, independent of transcription factors c-MYC and E2F in these cells; instead all-trans-retinoic acid (ATRA), a drug used for terminally differentiating AML subtypes, markedly suppressed miR-17-92 expression and increased PHLPP2 protein levels and phosphatase activity. Finally, we demonstrate that the effect of ATRA on miR-17-92 expression is mediated through its target, transcription factor C/EBPβ, which interacts with the intronic promoter of the miR-17-92 gene to inhibit transactivation of the cluster. These studies reveal a novel mechanism for upregulation of the phosphatase activity of PHLPP2 through C/EBPβ-mediated repression of the miR-17-92 cluster in terminally differentiating myeloid cells. Phosphatases are pivotal components of intracellular signaling cascades, controlling essential processes like metabolism, apoptosis, proliferation and differentiation. 1 The PH-domain leucine-rich repeat protein phosphatase (PHLPP) family serine-threonine phosphatases are emerging as central factors in cell survival and death regulation. The PHLPP2 is a member of this family. 2,3 To date four PHLPP substrates, Akt, PKC, Mst1 and S6K1, have been identified, all kinases involved in cell survival or apoptosis. 4-7 Dephosphorylation inactivates Akt, S6K1 and PKC, and subsequently cell survival signaling, whereas dephosphorylation of Mst1 activates its apoptotic function.PHLPP protein expression and activity is suppressed through various mechanisms in cancers. Although most studies on PHLPP2 have focused on genetic alterations in solid tumors, 8 PHLPP2 protein expression in small cell lung and colorectal cancers is also restricted through translational suppression 9 and post-transcriptional control by microRNAs (miR or miRNAs), miR-205 and miR-224. 10,11 The PHLPP2 3' untranslated region (3'UTR) harbors complementary binding sites for a subset of miRNAs belonging to the miRNA-17-92 cluster. 12 This cluster comprises six miRNAs on chromosome 13, transcribed as a single polycistronic unit. 13,14 Also known as oncomir-1, the cluster enhances cell proliferation or inhibits apoptosis by suppressing targets such as Bim, E2F1 and PTEN and is markedly overexpressed in human cancers. [15][16][17][18][19][20][21] Reduced levels of PHLPP2 in chemoresistant miR-17-92 overexpressing mantle cell lymphomas had suggested that the phosphatase could be a target of oncomir-1. 12 Kno...

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Pharmacokinetics of Low-Dose All-trans Retinoic Acid in Japanese Children with Cancer

Takitani

Inoue²,

Koh³

et al. 2004

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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SummaryAll-traps retinoic acid (ATRA) is used as differentiation therapy for acute pro myelocytic leukemia (APL). The two major adverse effects of ATRA therapy are hyperleuko cytosis and retinoic acid syndrome. In order to prevent these adverse effects, low-dose ATRA therapy (25mg/m2/d) has been tried in adults. Accordingly we assessed the pharmacoki netics of low-dose ATRA in children with cancer. Four children (one with APL and three with other advanced cancer) were administered ATRA and its pharmacokinetics were eval uated. In three patients, the pharmacokinetic parameters of ATRA were similar to those previously determined for APL patients in remission, but the values were lower in one patient. Low-dose ATRA was effective for APL, but not for the solid tumors. This therapy did not cause any severe toxicity. Further studies are needed to determine the optimum ATRA regimen and to evaluate low-dose ATRA combined with chemotherapy in children with APL.

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Expression of retinoic acid receptor–target genes during retinoic acid therapy for acute promyelocytic leukemia

Cited by 3 publications

References 9 publications

A novel function of B‐cell translocation gene 1 ( BTG1 ) in the regulation of hepatic insulin sensitivity in mice via c‐Jun

A novel function of B‐cell translocation gene 1 ( BTG1 ) in the regulation of hepatic insulin sensitivity in mice via c‐Jun

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

Pharmacokinetics of Low-Dose All-trans Retinoic Acid in Japanese Children with Cancer

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