Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurexins are polymorphic synaptic membrane proteins generated by alternative splicing of transcripts from six promoters in three genes (two promoters in each gene) at five canonical sites. Neurexins and factors regulating their alternative splicing may orchestrate coordinated presynaptic and postsynaptic development. Bioinformatic analysis revealed several sequence elements that could be involved in the regulation of alternative splicing at splice site 4 (SS#4); among them elements suspected as intronic binding sites of polypyrimidine tract binding protein (PTB), and its neuron specific analog nPTB. The role of nPTB in neurexin-2alpha and beta SS#4 splicing were studied using small interfering RNA (siRNA) to silence nPTB expression. Transformed rat retinal ganglion (RGC-5) cells expressed nPTB, PTB and neurexin-2alpha (mostly exon 20 excluded form) but not neurexin-2beta. Mouse spinal-cord glioma hybrid (NSC-34) cells expressed nPTB, PTB and both neurexin-2alpha and beta (mostly exon 20 included form). nPTB-siRNA inhibited nPTB but not PTB expression and significantly enhanced neurexin-2alpha SS# 4 exon-excluded transcript in both cell types. Neurexin-2beta SS#4 splicing was not affected by nPTB-siRNA. These results show a role for nPTB in neurexin-2alpha alternative splicing. The differential enhancement of SS# 4 exon exclusion in neurexin-2alpha suggests that the effects of nPTB are mediated via additional site(s) present in neurexin-2alpha but not in the shorter, beta form.
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PMID:Alternative splicing of neurexins: a role for neuronal polypyrimidine tract binding protein. 1853 53

Circular RNAs (circRNAs) have recently emerged as a new class of RNAs, highly enriched in the brain and very stable within cells, exosomes and body fluids. To analyze their involvement in glioblastoma multiforme (GBM) pathogenesis, we assayed the expression of twelve circRNAs, physiologically enriched in several regions of the brain, through real-time PCR in a cohort of fifty-six GBM patient biopsies and seven normal brain parenchymas. We focused on hsa_circ_0001445 (circSMARCA5): it was significantly downregulated in GBM biopsies as compared to normal brain tissues (p-value < 0.00001, student's t-test), contrary to its linear isoform counterpart that did not show any differential expression (p-value = 0.694, student's t-test). Analysis of a public dataset revealed a negative correlation between the expression of circSMARCA5 and glioma's histological grade, suggesting its potential negative role in the progression to malignancy. Overexpressing circSMARCA5 in U87MG cells significantly decreased their migration, but not their proliferation rate. In silico scanning of circSMARCA5 sequence revealed an enrichment in binding motifs for several RNA binding proteins (RBPs), specifically involved in splicing. Among them, serine and arginine rich splicing factor 1 (SRSF1), a splicing factor known to be a positive controller of cell migration and known to be overexpressed in GBM, was predicted to bind circSMARCA5 by three different prediction tools. Direct interaction between circSMARCA5 and SRSF1 is supported by enhanced UV crosslinking and immunoprecipitation (eCLIP) data for SRSF1 in K562 cells from Encyclopedia of DNA Elements (ENCODE). Consistently, U87MG overexpressing circSMARCA5 showed an increased expression of serine and arginine rich splicing factor 3 (SRSF3) RNA isoform containing exon 4, normally skipped in a SRSF1-dependent manner, resulting in a non-productive non-sense mediated decay (NMD) substrate. Interestingly, SRSF3 is known to interplay with two other splicing factors, polypyrimidine tract binding protein 1 (PTBP1) and polypyrimidine tract binding protein 2 (PTBP2), that positively regulate glioma cells migration. Collectively, our data show circSMARCA5 as a promising druggable tumor suppressor in GBM and suggest that it may exert its function by tethering the RBP SRSF1.
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PMID:CircSMARCA5 Inhibits Migration of Glioblastoma Multiforme Cells by Regulating a Molecular Axis Involving Splicing Factors SRSF1/SRSF3/PTB. 2941 69