Abstract：
:Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.
journal_name
Genes Devjournal_title
Genes & developmentauthors
Huang X,Dubuc AM,Hashizume R,Berg J,He Y,Wang J,Chiang C,Cooper MK,Northcott PA,Taylor MD,Barnes MJ,Tihan T,Chen J,Hackett CS,Weiss WA,James CD,Rowitch DH,Shuman MA,Jan YN,Jan LYdoi
10.1101/gad.193789.112subject
Has Abstractpub_date
2012-08-15 00:00:00pages
1780-96issue
16eissn
0890-9369issn
1549-5477pii
gad.193789.112journal_volume
26pub_type
杂志文章abstract：:Polycomb response elements (PREs) are specific cis-regulatory sequences needed for transcriptional repression of HOX and other target genes by Polycomb group (PcG) proteins. Among the many PcG proteins known in Drosophila, Pho is the only sequence-specific DNA-binding protein. To gain insight into the function of Pho,...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.377406
更新日期：2006-05-01 00:00:00
abstract：:Different RNA species are exported from the nucleus by distinct mechanisms. Among the different RNAs, mRNAs and major spliceosomal U snRNAs share several structural similarities, yet they are exported by distinct factors. We previously showed that U1 snRNAs behaved like an mRNA in nuclear export if various approximate...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1216204
更新日期：2004-09-01 00:00:00
abstract：:Heparan sulfate proteoglycans have been implicated in the presentation of a number of secreted signaling molecules to their signal-transducing receptors. We have characterized a gene trap mutation in the gene encoding a heparan sulfate biosynthetic enzyme, heparan sulfate 2-sulfotransferase (HS2ST). Transgenic mice we...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.12.12.1894
更新日期：1998-06-15 00:00:00
abstract：:Transcription by RNA polymerase II (RNAPII) is a dynamic process with frequent variations in the elongation rate. However, the physiological relevance of variations in RNAPII elongation kinetics has remained unclear. Here we show in yeast that a RNAPII mutant that reduces the transcription elongation rate causes wides...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.337212.120
更新日期：2020-07-01 00:00:00
abstract：:Although Apc is well characterized as a tumor-suppressor gene in the intestine, the precise mechanism of this suppression remains to be defined. Using a novel inducible Ahcre transgenic line in conjunction with a loxP-flanked Apc allele we, show that loss of Apc acutely activates Wnt signaling through the nuclear accu...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.287404
更新日期：2004-06-15 00:00:00
abstract：:Early endoderm formation in zebrafish requires at least three loci that function downstream of Nodal signaling but upstream of the early endodermal marker sox17: bonnie and clyde (bon), faust (fau), and casanova (cas). cas mutants show the most severe phenotype as they do not form any gut tissue and lack all sox17 exp...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.892301
更新日期：2001-06-15 00:00:00
abstract：:Joints form within the developing skeleton through the segmentation and cavitation of initially continuous cartilage condensations. However, the molecular pathways controlling joint formation largely remain to be clarified. In particular, while several critical secreted signals have been identified, no transcription f...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.209239.112
更新日期：2013-03-01 00:00:00
abstract：:Calcineurin, a conserved Ca(2+)/calmodulin-regulated protein phosphatase, plays a crucial role in Ca(2+) signaling in a wide variety of cell types. In Saccharomyces cerevisiae, calcineurin positively regulates transcription in response to stress by dephosphorylating the transcription factor Crz1p/Tcn1p. Dephosphorylat...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.967602
更新日期：2002-03-01 00:00:00
abstract：:Nonsense-mediated mRNA decay (NMD) is a quality control mechanism that detects and degrades mRNAs containing premature stop codons (PTCs). In vertebrates, PTCs trigger efficient NMD when located upstream of an exon junction complex (EJC). Degradation of PTC-containing mRNAs requires the endonucleolytic activity of SMG...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.604610
更新日期：2010-11-01 00:00:00
abstract：:To investigate the importance of sequences between the yeast (Saccharomyces cerevisiae) branch point (TACTAAC box) and 3' splice site (AG), we generated a series of pre-mRNA substrates that differed in the length of RNA retained on the 3' side of the TACTAAC box. These pre-mRNAs were compared as substrates for the fir...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1.3.238
更新日期：1987-05-01 00:00:00
abstract：:The bcl-6 proto-oncogene encodes a POZ/zinc finger transcriptional repressor expressed in germinal center (GC) B and T cells and required for GC formation and antibody affinity maturation. Deregulation of bcl-6 expression by chromosomal rearrangements and point mutations of the bcl-6 promoter region are implicated in ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.12.13.1953
更新日期：1998-07-01 00:00:00
abstract：:The enzyme telomerase, which elongates chromosome termini, is a critical factor in determining long-term cellular proliferation and tissue renewal. Hence, even small differences in telomerase levels can have substantial consequences for human health. In budding yeast, telomerase consists of the catalytic Est2 protein ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.246256.114
更新日期：2014-10-01 00:00:00
abstract：:The N-myc gene encodes a putative transcription factor that is thought to function in the regulation of gene expression during cell differentiation and/or growth. To examine the role of N-myc during development, we have used targeted mutagenesis in embryonic stem cells to produce a mouse line that carries an N-myc nul...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.6.12a.2248
更新日期：1992-12-01 00:00:00
abstract：:Dosage compensation is a process required to balance the expression of X-linked genes between males and females. In Drosophila this is achieved by targeting the dosage compensation complex or the male-specific lethal (MSL) complex to the male X chromosome. In order to study the mechanism of targeting, we have studied ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.430807
更新日期：2007-08-15 00:00:00
abstract：:The mammalian high mobility group proteins HMG1 and HMG2 are abundant, chromatin-associated proteins whose cellular function is not known. In this study we show that these proteins can substitute for the prokaryotic DNA-bending protein HU in promoting the assembly of the Hin invertasome, an intermediate structure in H...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.7.8.1521
更新日期：1993-08-01 00:00:00
abstract：:The human Y-family DNA polymerases, Poliota, Poleta, and Polkappa, function in promoting replication through DNA lesions. However, because of their low fidelity, any involvement of these polymerases in DNA synthesis during base excision repair (BER) would be highly mutagenic. Mechanisms, therefore, must exist to exclu...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1146103
更新日期：2003-11-15 00:00:00
abstract：:The kinases ATM and ATR (Tel1 and Mec1 in the yeast Saccharomyces cerevisiae) control the response to DNA damage. We report that S. cerevisiae Tel2 acts at an early step of the TEL1/ATM pathway of DNA damage signaling. We show that Tel1 and Tel2 interact, and that even when Tel1 protein levels are high, this interacti...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1646208
更新日期：2008-04-01 00:00:00
abstract：:We have studied the sequence requirements for 3'-end formation of rDNA transcripts in a cell-free system and show that the generation of correct ends of mouse pre-rRNA is brought about by a two-step process that involves a bona fide termination reaction, followed by a specific trimming of the primary transcript by 10 ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.3.2.224
更新日期：1989-02-01 00:00:00
abstract：:We have studied the effect of exogenous expression of the basal transcription factor TFIID on the activities of several different TATA-containing and TATA-lacking promoters. Overexpression of TFIID from a transfected plasmid in Drosophila Schneider cells resulted in substantial concentration-dependent increases in exp...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.6.2.304
更新日期：1992-02-01 00:00:00
abstract：:Neuronal depolarization and CaM kinase IV signaling alter the splicing of multiple exons in transcripts for ion channels, neurotransmitter receptors, and other synaptic proteins. These splicing changes are mediated in part by special CaM kinase-responsive RNA elements, within or adjacent to exons that are repressed in...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1837009
更新日期：2009-10-01 00:00:00
abstract：:Regulated cell expansion is an important determinant of organ shape in higher plants. The sabre mutation results in abnormal cell expansion in Arabidopsis. There is a shift in the orientation of expansion evident primarily in root cortex cells. The SABRE gene has been cloned and found to encode a novel protein. Reduct...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.9.3.330
更新日期：1995-02-01 00:00:00
abstract：:Although branchpoint recognition is an essential component of intron excision during the RNA splicing process, the branchpoint itself is frequently assumed to be a basal, rather than regulatory, sequence feature. However, this assumption has not been systematically tested due to the technical difficulty of identifying...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.312058.118
更新日期：2018-04-01 00:00:00
abstract：:Alternative pre-mRNA splicing determines many changes in gene expression during development. Two regulators known to control splicing patterns during neuron and muscle differentiation are the polypyrimidine tract-binding protein (PTB) and its neuronal homolog nPTB. These proteins repress certain exons in early myoblas...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1500707
更新日期：2007-01-01 00:00:00
abstract：:Deletions and other chromosomal rearrangements can be generated by recombination between repeated sequences. It has been shown in a number of systems that the probability of exchange or gene conversion decreases with increasing distance between repeats. This paper examines the question of how repeats find each other, ...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.2.12b.1800
更新日期：1988-12-01 00:00:00
abstract：:We have investigated the DNA-binding, oligomerization, and trans-activation functions of isolated segments of murine p53. We find that p53 has two autonomous DNA-binding regions. One domain, from amino acid 280 to 390, forms stable tetramers and binds DNA nonspecifically. The biological significance, if any, of this D...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.7.12b.2575
更新日期：1993-12-01 00:00:00
abstract：:The timing of asexual fruiting body formation during Aspergillus nidulans colony development is precisely regulated so that conidiophores are typically produced 1-2 mm behind the growing edge of the colony. Mutations in any of four A. nidulans genes, flbB, flbC, flbD, or flbE, result in colonies that are delayed at le...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.9.4.491
更新日期：1995-02-15 00:00:00
abstract：:The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that control intracellular cholesterol homeostasis through catabolism and transport. In this report, we...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.844900
更新日期：2000-11-15 00:00:00
abstract：:Tuberous sclerosis (TSC) is an autosomal dominant disease characterized by hamartoma formation in various organs and is caused by mutations targeting either the TSC1 or TSC2 genes. TSC1 and TSC2 proteins form a functionally interdependent dimeric complex. Phosphorylation of either TSC subunit by different kinases regu...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.1624008
更新日期：2008-04-01 00:00:00
abstract：:The mammary tumor-associated proto-oncogene Wnt-1/int-1 encodes a secreted protein implicated in the regulation of neural development in vertebrates and segmental pattern in Drosophila. Using a PCR-based strategy, we isolated cDNAs encoding six novel, related proteins that are expressed in fetal mice. Predicted protei...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.4.12b.2319
更新日期：1990-12-01 00:00:00
abstract：:TGF-β receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformati...
journal_title：Genes & development
pub_type： 杂志文章
doi：10.1101/gad.330837.119
更新日期：2019-11-01 00:00:00
