N-MYC promotes cell proliferation through a direct transactivation of neuronal leucine-rich repeat protein-1 (NLRR1) gene in neuroblastoma

Hossain, Md. Shamim; Ozaki, Toshinori; Wang, H; Nakagawa, Atsuko; Takenobu, Hisanori; Ohira, Miki; Nakagawara, Akira

doi:10.1038/onc.2008.200

Cited by 36 publications

(39 citation statements)

References 24 publications

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“…We previously reported that mRNA expression levels of NLRR1 are significantly higher in unfavorable neuroblastoma (12). We further reported that NLRR1 protein expression is higher in MYCN-amplified primary neuroblastomas than in nonamplified tumors, and that MYCN can transcriptionally upregulate NLRR1 (14). We also found that overexpression of NLRR1 promoted neuroblastoma cell proliferation and inhibited cellular apoptosis upon serum starvation (14).…”

Section: Introductionmentioning

confidence: 61%

“…We further reported that NLRR1 protein expression is higher in MYCN-amplified primary neuroblastomas than in nonamplified tumors, and that MYCN can transcriptionally upregulate NLRR1 (14). We also found that overexpression of NLRR1 promoted neuroblastoma cell proliferation and inhibited cellular apoptosis upon serum starvation (14). NLRR family proteins have also been considered as cell adhesion or signaling molecules, and mouse NLRR3 functions in EGF-mediated activation of extracellular signal-regulated kinase (ERK; ref.…”

Section: Introductionmentioning

confidence: 81%

“…Our previous report showed that NLRR1 is a direct transcriptional target of MYCN in neuroblastoma, and is associated with cell proliferation and survival (14). However, the mechanism by which NLRR1 regulates cell proliferation was still unknown.…”

Section: Nlrr1 Enhances Egf/igf-mediated Cell Proliferation In Neurobmentioning

confidence: 99%

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NLRR1 Enhances EGF-Mediated MYCN Induction in Neuroblastoma and Accelerates Tumor Growth In Vivo

et al. 2012

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Neuronal leucine-rich repeat protein-1 (NLRR1), a type-1 transmembrane protein highly expressed in unfavorable neuroblastoma, is a target gene of MYCN that is predominately expressed in primary neuroblastomas with MYCN amplification. However, the precise biological role of NLRR1 in cell proliferation and tumor progression remains unknown. To investigate its functional importance, we examined the role of NLRR1 in EGF and insulin growth factor-1 (IGF-1)-mediated cell viability. We found that NLRR1 positively regulated cell proliferation through activation of extracellular signal-regulated kinase mediated by EGF and IGF-1. Interestingly, EGF stimulation induced endogenous MYCN expression through Sp1 recruitment to the MYCN promoter region, which was accelerated in NLRR1-expressing cells. The Sp1-binding site was identified on the promoter region for MYCN induction, and phosphorylation of Sp1 was important for EGF-mediated MYCN regulation. In vivo studies confirmed the proliferation-promoting activity of NLRR1 and established an association between NLRR1 expression and poor prognosis in neuroblastoma. Together, our findings indicate that NLRR1 plays an important role in the development of neuroblastoma and therefore may represent an attractive therapeutic target for cancer treatment. Cancer Res; 72(17); 4587-96. Ó2012 AACR.

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Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 81%

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NLRR1 Enhances EGF-Mediated MYCN Induction in Neuroblastoma and Accelerates Tumor Growth In Vivo

et al. 2012

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“…As ectopic expression of NLRR3 induced morphologic changes indicative of neuronal differentiation accompanying with neurite outgrowth (data not shown), the downregulation of NLRR3 by MYCN might contribute to the well-documented stimulation of cell proliferation by MYCN. Although there are MYCN target genes that are potentially involved in cell-cycle progression, including a-prothymosin, ornithine decarboxylase, MCM7, ID2, MDM2, and NLRR1 (27,36,(45)(46)(47), suppression of NLRR3 might have an additive effect on NBL cell proliferation. Our log-rank test showed that expression of NLRR3 is well associated with a favorable prognosis, suggesting its involvement in NBL differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…The amino acid sequences of NLRR family proteins are highly conserved in the extracellular domains, and NLRR1 and NLRR3 also possess a conserved stretch of 11 amino acids with 2 clathrin adapter interaction domains and a dileucine-type domain in the short intracellular region (25,26), which might provide a basis for NLRR function. Our previous reports showed that NLRR1 is a direct transcriptional target of MYCN and that a high expression level of NLRR1 mRNA is associated with a poor prognosis of NBL (23,27). However, the function of NLRR3 is poorly understood except that mouse NLRR3 expression is increased in the cerebral cortex after a cortical brain injury (28) and that rat NLRR3 may be involved in the regulation of EGF receptor signaling through interaction with clathrins (26).…”

Section: Introductionmentioning

confidence: 99%

Expression of NLRR3 Orphan Receptor Gene Is Negatively Regulated by MYCN and Miz-1, and Its Downregulation Is Associated with Unfavorable Outcome in Neuroblastoma

Akter

Takatori

Hossain

et al. 2011

Clinical Cancer Research

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Purpose: Our previous study showed that expression of NLRR3 is significantly high in favorable neuroblastomas (NBL), whereas that of NLRR1 is significantly high in unfavorable NBLs. However, the molecular mechanism of transcriptional regulation of NLRR3 remains elusive. This study was undertaken to clarify the transcriptional regulation of NLRR3 and its association with the prognosis of NBL.Experimental Design: NLRR3 and MYCN expressions in NBL cell lines were analyzed after induction of cell differentiation, MYCN knockdown, and overexpression. The transcriptional regulation of NLRR3 was analyzed by luciferase reporter and chromatin immunoprecipitation assays. Quantitative PCR was used for examining the expression of NLRR3, Miz-1, or MYCN in 87 primary NBLs.Results: The expression of NLRR3 mRNA was upregulated during differentiation of NBL cells induced by retinoic acid, accompanied with reduced expression of MYCN, suggesting that NLRR3 expression was inversely correlated with MYCN in differentiation. Indeed, knockdown of MYCN induced NLRR3 expression, whereas exogenously expressed MYCN reduced cellular NLRR3 expression. We found that Miz-1 was highly expressed in favorable NBLs and NLRR3 was induced by Miz-1 expression in NBL cells. MYCN and Miz-1 complexes bound to NLRR3 promoter and showed a negative regulation of NLRR3 expression. In addition, a combination of low expression of NLRR3 and high expression of MYCN was highly associated with poor prognosis.Conclusions: NLRR3 is a direct target of MYCN, which associates with Miz-1 and negatively regulates NLRR3 expression. NLRR3 may play a role in NBL differentiation and the survival of NBL patients by inversely correlating with MYCN amplification.

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Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

Winther

Walmod

2013

Advances in Neurobiology

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Leucine-rich repeats (LRRs) are motifs that form protein-ligand interaction domains. There are approximately 140 human genes encoding proteins with extracellular LRRs. These encode cell adhesion molecules (CAMs), proteoglycans, G-protein-coupled receptors, and other types of receptors. Here we give a brief description of 36 proteins with extracellular LRRs that all can be characterized as CAMs or putative CAMs expressed in the nervous system. The proteins are involved in multiple biological processes in the nervous system including the proliferation and survival of cells, neuritogenesis, axon guidance, fasciculation, myelination, and the formation and maintenance of synapses. Moreover, the proteins are functionally implicated in multiple diseases including cancer, hearing impairment, glaucoma, Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism spectrum disorders, schizophrenia, and obsessive-compulsive disorders. Thus, LRR-containing CAMs constitute a large group of proteins of pivotal importance for the development, maintenance, and regeneration of the nervous system.

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N-MYC promotes cell proliferation through a direct transactivation of neuronal leucine-rich repeat protein-1 (NLRR1) gene in neuroblastoma

Cited by 36 publications

References 24 publications

NLRR1 Enhances EGF-Mediated MYCN Induction in Neuroblastoma and Accelerates Tumor Growth In Vivo

NLRR1 Enhances EGF-Mediated MYCN Induction in Neuroblastoma and Accelerates Tumor Growth In Vivo

Expression of NLRR3 Orphan Receptor Gene Is Negatively Regulated by MYCN and Miz-1, and Its Downregulation Is Associated with Unfavorable Outcome in Neuroblastoma

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

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