PAX5 is the transcriptional activator of mucolipin-2 (MCOLN2) gene

Valadez, Jessica; Cuajungco, Math P.

doi:10.1016/j.gene.2014.11.003

Cited by 16 publications

(19 citation statements)

References 43 publications

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“…TRPML-2 protein localizes both in the plasma membrane and in the cytoplasm. In line with our findings, the transcriptional activator of the TRPML-2 gene [26], Paired box 5 (PAX5), also known as B-cell lineage specific activator protein, has been found to be overexpressed in human astrocytoma tissues, and its expression correlates with increasing malignancy and pathological grade [27]. The PAX proteins promote tumor cell survival, proliferation and apoptosis resistance and a reduction in PAX gene expression induces apoptosis in tumor cells [28, 29].…”

Section: Discussionsupporting

confidence: 89%

Overexpression of transient receptor potential mucolipin-2 ion channels in gliomas: role in tumor growth and progression

et al. 2016

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The Transient Receptor Potential (TRP) superfamily consists of cation-selective and non-selective ion channels playing an important role both in sensory physiology and in physiopathology in several complex diseases including cancers. Among TRP family, the mucolipin (TRPML1, −2, and −3) channels represent a distinct subfamily of endosome/lysosome Ca2+ channel proteins. Loss-of-function mutations in human TRPML-1 gene cause a neurodegenerative disease, Mucolipidosis Type IV, whereas at present no pathology has been associated to human TRPML-2 channels.Herein we found that human TRPML-2 is expressed both in normal astrocytes and neural stem/progenitor cells. By quantitative RT-PCR, western blot, cytofluorimetric and immunohistochemistry analysis we also demonstrated that TRPML-2 mRNA and protein are expressed at different levels in glioma tissues and high-grade glioma cell lines of astrocytic origin. TRPML-2 mRNA and protein levels increased with the pathological grade, starting from pylocitic astrocytoma (grade I) to glioblastoma (grade IV). Moreover, by RNA interference, we demonstrated a role played by TRPML-2 in survival and proliferation of glioma cell lines. In fact, knock-down of TRPML-2 inhibited the viability, altered the cell cycle, reduced the proliferation and induced apoptotic cell death in glioma cell lines. The DNA damage and apoptosis induced by TRPML-2 loss increased Ser139 H2AX phosphorylation and induced caspase-3 activation; furthermore, knock-down of TRPML-2 in T98 and U251 glioma cell lines completely abrogated Akt and Erk1/2 phosphorylation, as compared to untreated cells.Overall, the high TRPML-2 expression in glioma cells resulted in increased survival and proliferation signaling, suggesting a pro-tumorigenic role played by TRPML-2 in glioma progression.

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Section: Discussionsupporting

confidence: 89%

Overexpression of transient receptor potential mucolipin-2 ion channels in gliomas: role in tumor growth and progression

et al. 2016

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“…Although the function of MCOLN2 is unclear, the B-cell lineage specific activator PAX5 regulates its expression, strongly implicating its involvement in early Bcell development. 41 Taken together, the downregulation of these genes due to DNA methylation may play important roles in the development of ALL.…”

Section: Discussionmentioning

confidence: 99%

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

et al. 2015

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Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children under the age of 15. In addition to genetic aberrations, epigenetic modifications such as DNA methylation are altered in cancer and impact gene expression. To identify epigenetic alterations in ALL, genome-wide methylation profiles were generated using the methylated CpG island recovery assay followed by next-generation sequencing. More than 25,000 differentially methylated regions (DMR) were observed in ALL patients with »90% present within intronic or intergenic regions. To determine the regulatory potential of the DMR, whole-transcriptome analysis was performed and integrated with methylation data. Aberrant promoter methylation was associated with the altered expression of genes involved in transcriptional regulation, apoptosis, and proliferation. Novel enhancer-like sequences were identified within intronic and intergenic DMR. Aberrant methylation in these regions was associated with the altered expression of neighboring genes involved in cell cycle processes, lymphocyte activation and apoptosis. These genes include potential epi-driver genes, such as SYNE1, PTPRS, PAWR, HDAC9, RGCC, MCOLN2, LYN, TRAF3, FLT1, and MELK, which may provide a selective advantage to leukemic cells. In addition, the differential expression of epigenetic modifier genes, pseudogenes, and non-coding RNAs was also observed accentuating the role of erroneous epigenetic gene regulation in ALL.

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“…Focusing on MCOLN2 , our analysis of its genomic DNA spanning the 5’ untranslated region (UTR) and putative promoter region upstream of the transcriptional start site (TSS) revealed two predicted CpG islands: a 630 basepair (bp) long sequence located at −963 bp upstream of the TSS, and 1,182 bp long sequence located at −780 bp that also flanks the 5’-UTR, and parts of the gene (Fig. 3A) [106]. We identified three GC boxes but no TATA box within the putative promoter region, and our subsequent dual-luciferase reporter assays showed the core promoter region to be between −79 and −52 bp upstream of the TSS [106].…”

Section: Trpml2 and Its Potential Role In Immune Cell Development Fumentioning

confidence: 99%

“…3A) [106]. We identified three GC boxes but no TATA box within the putative promoter region, and our subsequent dual-luciferase reporter assays showed the core promoter region to be between −79 and −52 bp upstream of the TSS [106]. Using the JASPAR and TRANSFAC online databases, we narrowed down five transcription factors (TFs) predicted to bind the DNA sequence spanning −79 and −52 bp, namely, CTCF, KLF4, MZF1, NF-κB1, and BSAP (also known as PAX5) (Fig.…”

Section: Trpml2 and Its Potential Role In Immune Cell Development Fumentioning

confidence: 99%

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The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function

Cuajungco

Silva

Habibi

et al. 2015

Pflugers Arch - Eur J Physiol

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The discovery of the TRPML subfamily of ion channels has created an exciting niche in the fields of membrane trafficking, signal transduction, autophagy, and metal homeostasis. The TRPML protein subfamily consist three members, TRPML1, -2, and -3, which are encoded by MCOLN1, -2, and -3 genes, respectively. They are non-selective cation channels with six predicted transmembrane domains, and intracellular amino- and carboxyl-terminus regions. They localize to the plasma membrane, endosomes, and lysosomes of cells. TRPML1 is associated with the human lysosomal storage disease known as Mucolipidosis type IV (MLIV), but TRPML2 and TRPML3 have not been linked with a human disease. Although TRPML1 is expressed in many tissues, TRPML3 is expressed in a varied but limited set of tissues, while TRPML2 has a more limited expression pattern where it is mostly detected in lymphoid and myeloid tissues. This review focuses on TRPML2 because it appears to play an important, yet unrecognized role in the immune system. While the evidence has been mostly indirect, we present and discuss relevant data that strengthen the connection of TRPML2 with cellular immunity. We also discuss the functional redundancy between the TRPML proteins, and how such features could be exploited as a potential therapeutic strategy for MLIV disease. We present evidence that TRPML2 expression may complement certain phenotypic alterations in MLIV cells, and briefly examine the challenges of functional complementation. In conclusion, the function of TRPML2 still remains obscure, but emerging data show that it may serve a critical role in immune cell development and inflammatory responses.

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PAX5 is the transcriptional activator of mucolipin-2 (MCOLN2) gene

Cited by 16 publications

References 43 publications

Overexpression of transient receptor potential mucolipin-2 ion channels in gliomas: role in tumor growth and progression

Overexpression of transient receptor potential mucolipin-2 ion channels in gliomas: role in tumor growth and progression

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

The mucolipin-2 (TRPML2) ion channel: a tissue-specific protein crucial to normal cell function

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