Abstract
Pseudokinases, comprising 10% of the human kinome, are emerging as regulators of canonical kinases and their functions are starting to be defined. We previously identified the pseudokinase Nuclear Receptor Binding Protein 2 (NRBP2) in a screen for genes regulated during neural differentiation. During mouse brain development, NRBP2 is expressed in the cerebellum, and in the adult brain, mainly confined to specific neuronal populations. To study the role of NRBP2 in brain tumors, we stained a brain tumor tissue array for NRPB2, and find its expression to be low, or absent, in a majority of the tumors. This includes medulloblastoma (MB), a pediatric tumor of the cerebellum. Using database mining of published MB data sets, we also find that NRBP2 is expressed at a lower level in MB than in the normal cerebellum. Recent studies indicate that MB exhibits frequent epigenetic alternations and we therefore treated MB cell lines with drugs inhibiting DNA methylation or histone deacetylation, which leads to an upregulation of NRBP2 mRNA expression, showing that it is under epigenetic regulation in cultured MB cells. Furthermore, forced overexpression of NRBP2 in MB cell lines causes a dramatic decrease in cell numbers, increased cell death, impaired cell migration and inhibited cell invasion in vitro. Taken together, our data indicate that downregulation of NRBP2 may be a feature by which MB cells escape growth regulation.
Highlights
Medulloblastoma (MB) is the most common pediatric malignant brain tumor, located in the cerebellum
We previously reported that malignant brain tumors and neural stem- and progenitor cells (NSPCs) share a common transcriptional signature, and selected the pseudokinase nuclear receptor binding protein 2 (NRBP2) for further study because of its high level of regulation during differentiation of NSPCs [6]
Because Nuclear Receptor Binding Protein 2 (NRBP2) expression in the mouse brain was higher in differentiated neurons and lower in stem cells, we hypothesized that it might be expressed at low levels in brain tumor cells, since cancer cells share many properties with NSPCs
Summary
Medulloblastoma (MB) is the most common pediatric malignant brain tumor, located in the cerebellum. Expression profiling of MB has shown overlapping gene signatures between cancer cells and stem cells, indicating similar gene regulatory networks in medulloblastoma and neural stem- and progenitor cells (NSPCs) [5]. We previously reported that malignant brain tumors and NSPCs share a common transcriptional signature, and selected the pseudokinase nuclear receptor binding protein 2 (NRBP2) for further study because of its high level of regulation during differentiation of NSPCs [6]. Expression of NRBP2 increases during mouse brain development, and in the cerebellum, NRBP2 is detected in the lining of the fourth ventricle, in a subset of Math1-positive precursor cells around birth, and in the Purkinje cell layer around postnatal day 10. Mature Purkinje cells in the adult mouse cerebellum are intensely stained for NRBP2 [7], and NRBP2 expression corresponds to neuronal maturation in the cerebellum
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