cAMP response element-binding protein promotes gliomagenesis by modulating the expression of oncogenic microRNA-23a

Tan, Xiaochao; Wang, Shan; Zhu, Liyuan; Wu, Chao; Yin, Bin; Zhao, Jizong; Yuan, Jing; Qiang, Boqin; Peng, Xiaozhong

doi:10.1073/pnas.1207787109

Cited by 108 publications

(93 citation statements)

References 48 publications

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“…These data are in line with recent studies demonstrating that CREB knockdown reduces cell survival and proliferation, and cell-cycle progression of different tumor cells (37)(38)(39), and they were further strengthened by the rescue of CREB expression in the shCREB-HER-2/neu þ cells, which reversed the untransformed morphology and growth characteristics (Fig. 2).…”

supporting

confidence: 91%

“…The reduced invasion potential and enhanced apoptotic activity in vitro was confirmed by the significant decrease and delayed tumor growth of the shCREB-HER-2/neu þ cells in vivo. These data are in line with results from a nude-mouse model in which the mice were injected with melanoma cells expressing dominant-negative CREB (12), in glioma cells transfected with shCREB (39), and in an artificial CREB model in which CREB Ser133 is mutated (53). Furthermore, the first own results analyzing the frequency of immune cells upon in vivo application of HER-2/neu þ cells and their counterpart shCREB-HER-2/neu þ cells suggest that CREB silencing also affects the immunogenicity of tumors and the antitumor immune response, which is currently being investigated in detail.…”

supporting

confidence: 87%

“…So far, initial studies testing the potential to target CREB as a strategy for cancer therapy have focused on approaches that inhibit CREB function by shRNAs or by using dominant-negative CREB mutants, which target the CREB-CBP interaction, thereby preceding the CREB-dependent transcriptional activation of gene expression. Indeed, inhibition of CREB activity by dominant-negative mutants or by shRNAs was associated with a reduced in vitro and in vivo growth potential and increased radiosensitivity (39,43,44). In the HER-2/neu model used, shCREB-mediated inhibition also resulted in decreased proliferation of HER-2/neu þ cells, accompanied by cell-cycle arrest, increased apoptosis, and reduced cell migration and invasion, which was directly associated with an altered expression of proapoptotic and antiapoptotic genes as well as a transcriptional downregulation of MMP-2 and -9 expression.…”

mentioning

confidence: 99%

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HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

Steven

Leisz

Massa

et al. 2013

Molecular Cancer Research

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The cyclic (c)AMP responsive element binding protein (CREB) plays a key role in many cellular processes, including differentiation, proliferation, and signal transduction. Furthermore, CREB overexpression was found in tumors of distinct origin and evidence suggests an association with tumorigenicity. To establish a mechanistic link between HER-2/neu-mediated transformation and CREB protein expression and function, in vitro models of HER-2/neu-overexpressing and HER-2/neu-negative/silenced counterparts as well as human mammary carcinoma lesions with defined HER-2/neu status were used. HER-2/neu overexpression resulted in the induction and activation of CREB protein in vitro and in vivo, whereas short hairpin RNA (shRNA)-mediated inhibition of HER-2/neu correlated with downregulated CREB activity. CREB activation in HER-2/neu-transformed cells enhanced distinct signal transduction pathways, whereas their inhibition negatively interfered with CREB expression and/or activation. CREB downregulation in HER-2/neu-transformed cells by shRNA and by the inhibitors KG-501 and lapatinib caused morphologic changes, reduced cell proliferation with G 0 -G 1 cell-cycle arrest, which was rescued by CREB expression. This was accompanied by reduced cell migration, wound healing, an increased fibronectin adherence, invasion, and matrix metalloproteinase expression. In vivo shCREB-HER-2/neu þ cells, but not control cells, exerted a significantly decreased tumorgenicity that was associated with decreased proliferative capacity, enhanced apoptosis, and increased frequency of T lymphocytes in peripheral blood mononuclear cells. Thus, CREB plays an important role in the HER-2/neu-mediated transformation by altering in vitro and in vivo growth characteristics.

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supporting

confidence: 91%

supporting

confidence: 87%

mentioning

confidence: 99%

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HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

Steven

Leisz

Massa

et al. 2013

Molecular Cancer Research

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“…Moreover, in human glioblastoma cell lines, CREB small interfering RNA treatment decreases miR-21 expression. 34 However, whether CREB directly regulates miR-21 promoter activity is not known. We have determined that CREB physically binds to the miR-21 promoter in mouse kidney cells, and mutating CREB binding sites or inhibiting cAMP signaling reduces the transcriptional activity of miR-21 promoter.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

Lakhia¹,

Hajarnis²,

Williams³

et al. 2015

JASN

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Autosomal dominant polycystic kidney disease (ADPKD), one of the most common monogenetic disorders, is characterized by kidney failure caused by bilateral renal cyst growth. MicroRNAs (miRs) have been implicated in numerous diseases, but the role of these noncoding RNAs in ADPKD pathogenesis is still poorly defined. Here, we investigated the role of miR-21, an oncogenic miR, in kidney cyst growth. We found that transcriptional activation of miR-21 is a common feature of murine PKD. Furthermore, compared with renal tubules from kidney samples of normal controls, cysts in kidney samples from patients with ADPKD had increased levels of miR-21. cAMP signaling, a key pathogenic pathway in PKD, transactivated miR-21 promoter in kidney cells and promoted miR-21 expression in cystic kidneys of mice. Genetic deletion of miR-21 attenuated cyst burden, reduced kidney injury, and improved survival of an orthologous model of ADPKD. RNA sequencing analysis and additional in vivo assays showed that miR-21 inhibits apoptosis of cyst epithelial cells, likely through direct repression of its target gene programmed cell death 4. Thus, miR-21 functions downstream of the cAMP pathway and promotes disease progression in experimental PKD. Our results suggest that inhibiting miR-21 is a potential new therapeutic approach to slow cyst growth in PKD.

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“…The present study revealed that elevated level of miR-23a in OLs is sufficient to promote formation of myelin that can last until older age (at least 1-y old) partly through the Akt/mTOR and MAPK signaling pathways by targeting PTEN. A recent study reported that the cAMP-response element-binding protein (CREB) promotes glioma formation by up-regulating miR-23a, leading to down-regulation of its direct target, PTEN (29). Thus far, we have not observed obviously increased incidence of glioma formation in murine brains overexpressing miR-23a in myelinating glia.…”

Section: Discussionmentioning

confidence: 53%

MicroRNA-23a promotes myelination in the central nervous system

Lin¹,

Huang

Zhang³

et al. 2013

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

110

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Demyelinating disorders including leukodystrophies are devastating conditions that are still in need of better understanding, and both oligodendrocyte differentiation and myelin synthesis pathways are potential avenues for developing treatment. Overexpression of lamin B1 leads to leukodystrophy characterized by demyelination of the central nervous system, and microRNA-23 (miR-23) was found to suppress lamin B1 and enhance oligodendrocyte differentiation in vitro. Here, we demonstrated that miR23a-overexpressing mice have increased myelin thickness, providing in vivo evidence that miR-23a enhances both oligodendrocyte differentiation and myelin synthesis. Using this mouse model, we explored possible miR-23a targets and revealed that the phosphatase and tensin homologue/phosphatidylinositol trisphosphate kinase/Akt/mammalian target of rapamycin pathway is modulated by miR-23a. Additionally, a long noncoding RNA, 2700046G09Rik, was identified as a miR-23a target and modulates phosphatase and tensin homologue itself in a miR-23a-dependent manner. The data presented here imply a unique role for miR-23a in the coordination of proteins and noncoding RNAs in generating and maintaining healthy myelin.M icroRNAs (miRNAs) play an important role in regulating a large number of developmental processes and diseases (1-3) through fine tuning biological networks (4, 5). Expression levels of miRNAs in oligodendroglia vary according to their differentiation stages, indicating a possible role for miRNAs in regulating developmental processes among migratory, proliferating, and myelinating oligodendrocytes (OLs) (6-9). Disruption of miRNA biogenesis by Dicer ablation in oligodendroglia at postdevelopmental stages results in a neurodegenerative phenotype including demyelination, inflammation, and axon loss (10), suggesting that miRNAs are also important for myelin maintenance at later developmental stages. miR-23 is among the most abundant miRNAs in OLs (6, 7). Previously, we reported that in the presence of excess miR-23 in vitro, a greater proportion of cells express mature markers of OLs that are paralleled by multipolar morphological appearance with increased levels of mature myelin proteins, indicating that miR-23 can enhance oligodendrogenesis (11). In contrast, excessive lamin B1, a nuclear envelope protein and target of miR-23, leads to lower numbers of cells expressing mature markers with reduced levels of mature myelin proteins both in vitro and in vivo, suggesting defective differentiation of OLs. Importantly, the adverse effects of lamin B1 on OL cells can be abrogated by overexpressing miR-23, which functions as a negative regulator of lamin B1.Here, we use mice in which miR-23a (one of the two miR-23 isoforms: miR-23a and b) overexpression is driven by an OLspecific promoter [2′,3′-cyclic nucleotide 3′-phophodiesterase (Cnp)] to investigate the effects of miR-23a on OL differentiation and myelin synthesis in vivo. We demonstrated that in addition to the previously identified target, lamin B1, miR-23a also directly modul...

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cAMP response element-binding protein promotes gliomagenesis by modulating the expression of oncogenic microRNA-23a

Cited by 108 publications

References 48 publications

HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

HER-2/neu Mediates Oncogenic Transformation via Altered CREB Expression and Function

MicroRNA-21 Aggravates Cyst Growth in a Model of Polycystic Kidney Disease

MicroRNA-23a promotes myelination in the central nervous system

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