Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of heterozygosity for 10q23-26 is seen in over 80% of glioblastoma multiforme tumors. We have used a positional cloning strategy to isolate a novel gene, LGI1 (Leucine-rich gene-Glioma Inactivated), which is rearranged as a result of the t(10;19)(q24;q13) balanced translocation in the T98G glioblastoma cell line lacking any normal chromosome 10. Rearrangement of the LGI1 gene was also detected in the A172 glioblastoma cell line and several glioblastoma tumors. These rearrangements lead to a complete absence of LGI1 expression in glioblastoma cells. The LGI1 gene encodes a protein with a calculated molecular mass of 60 kD and contains 3.5 leucine-rich repeats (LRR) with conserved flanking sequences. In the LRR domain, LGI1 has the highest homology with a number of transmembrane and extracellular proteins which function as receptors and adhesion proteins. LGI1 is predominantly expressed in neural tissues, especially in brain; its expression is reduced in low grade brain tumors and it is significantly reduced or absent in malignant gliomas. Its localization to the 10q24 region, and rearrangements or inactivation in malignant brain tumors, suggest that LGI1 is a candidate tumor suppressor gene involved in progression of glial tumors.
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PMID:A novel gene, LGI1, from 10q24 is rearranged and downregulated in malignant brain tumors. 987 93

The human LGI1 gene is a leucine-rich, repeat-containing gene that was cloned from the t(10:19) breakpoint of the T98G glioblastoma cell line. The LGI1 gene maps to 10q24, a region of peak LOH in malignant gliomas, and is inactivated during the transition from low to high-grade brain tumors. Here we report detailed studies of the genomic structure of the LGI1 gene and its promoter. We have also cloned and characterized the mouse lgil gene, which is 97% homologous to the human gene at the amino acid level and 91% homologous at the nucleotide level. LGI1 contains 8 exons, where each of the four leucine-rich repeat units is contained in an individual 72-bp exon. The cysteine-rich regions flanking the LRR and the single trans-membrane domain do not occupy individual exons. Approximately 5-kb of the genomic region 5' to LGI1 was sequenced, but conventional CAAT and TATA motifs were not present within this sequence. A 597-bp fragment of this 5' sequence was cloned upstream of a promoterless luciferase gene and was shown to be sufficient to drive transcription. SSCP analysis of the coding region of LGI1 in 20 glioblastomas and five cell lines did not reveal any mutations. Because LGI1 expression is considerably downregulated in gliomas, we also investigated whether this was owing to changes in the methylation status of the promoter. Southern blot analysis and 5-azacytidine treatment did not show any appreciable difference in methylation status between normal brain and glioblastomas.
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PMID:Identification of the promoter, genomic structure, and mouse ortholog of LGI1. 1092 Feb 29

Mutations in LGI1 have been linked to autosomal dominant partial epilepsy with auditory features (ADPEAF), an unusual inherited human partial epilepsy phenotype. In addition, decreases in LGI1 expression are observed in glioblastoma patient samples and glioblastoma cell lines. LGI1, one member of the LGI gene family, encodes a approximately 63 kDa protein, with strong regional expression in neurons within the temporal lobe. Although the function of LGI proteins remains unknown, structural analyses suggest that LGI1 could be either localized to the membrane or secreted. Here, we show that LGI1-4 exhibit overlapping patterns of diffuse mRNA expression in the adult mouse brain, with some areas of specific localization characteristic of each family member. We find robust secretion of mouse LGI1 protein following transfection into 293T cells. LGI family members, LGI3, LGI4 and a newly identified splice form of LGI2, LGI2B, are also secreted in culture, indicating that secretion is a conserved feature of this protein family. Introduction of mutations in LGI1, including those identified in ADPEAF pedigrees, reveals that the mutant proteins either are not secreted or are unstable. These results demonstrate loss-of-function as a pathogenic basis for LGI1-mediated ADPEAF.
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PMID:ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. 1585 55

The LGI1 gene has been implicated in the malignant progression of glioblastoma and it has also been genetically linked to a form of partial epilepsy (ADLTE). In this study, we investigated the relevance of LGI1 expression for neuroblastoma cells. The analysis of two cell lines (SH-SY5Y and SK-N-BE) revealed unpredictably low levels of LGI1 and stable cell transfection with LGI1 cDNA yielded moderate increases of LGI1 expression. Neuroblastoma cell clones exhibited impaired cell growth and survival ability in relation to LGI1 levels. The process of growth inhibition could be discerned under experimental conditions of low cell density, since conditions of elevated cell density, which enhance the requirement for survival stimuli, resulted in massive cellular death. At high cell density, spontaneous apoptosis of LGI1 cells was clearly shown by the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria and by phosphatydil serine exposure and nuclear fragmentation. Activation of apoptotic effectors caspase-3/7 also occurred, however, the broad caspase inhibitor Z-VAD-FMK substantially failed to block cell death. Thus the possibility that LGI1-triggered apoptosis may involve initiator caspases linked to activation of death receptors, appears unlikely. The decreased ratio of Bcl-2 to Bax suggests that apoptosis is initiated by the intrinsic mitochondrial pathway through the release of caspase-dependent and -independent apoptogenic molecules. This study provides the first evidence that LGI1 controls neuronal cell survival, suggesting its role in the development of the nervous system in relation to the pathogenesis of neuroblastoma and ADLTE.
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PMID:Increased expression of LGI1 gene triggers growth inhibition and apoptosis of neuroblastoma cells. 1651 56

Disruptions of LGI1 in glioblastoma (GBM) cell lines and LGI1 mutations in families with autosomal dominant epilepsy imply a role for LGI1 in glial cells as well as in neurons. Although we and others could not find LGI1 mutations in malignant gliomas, our initial studies appeared to support the idea that LGI1 is poorly expressed or absent in these tumors. Microarray data suggested that LGI1 could be involved in the control of matrix metalloproteinases, and we found that tumors derived from U87 glioblastoma cells overexpressing LGI1 were less aggressive than U87 control tumors. To our surprise, we observed that LGI1 expression after differentiation of murine neural stem cells was robust in neurons but negligible in glial cells, in agreement with immunohistochemistry studies on rodent brain. This observation could suggest that the variable levels of LGI1 expression in gliomas reflect the presence of neurons entrapped within the tumor. To test this hypothesis, we investigated LGI1 expression in parallel with expression of the neuronal marker NEF3 by real-time PCR on 30 malignant gliomas. Results showed a strong, positive correlation between the expression levels of these two genes (P < 0.0001). Thus, our data confirm that LGI1 is involved in cell-matrix interactions but suggest that its expression is not relevant in glial cells, implying that its role as a tumor suppressor in gliomas should be reconsidered.
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PMID:Expression studies in gliomas and glial cells do not support a tumor suppressor role for LGI1. 1653 56

The LGI1 gene was suggested to function as tumor suppressor for its ability to reduce malignant features of glioblastoma cells. In support to this proposal were the findings that overexpression of LGI1 in neuroblastoma cells inhibited proliferation and induced apoptosis. In this study we performed stable LGI1 expression in HeLa cells to examine whether the noxious effect of LGI1 might be extended to cancer cells of diverse origin. HeLa cell clones stably expressing LGI1 exhibited a significant impairment of proliferation and a consistent increase of cell death when compared with control cells lacking expression of LGI1. Expression of LGI1 increased the activity of apoptosis effectors caspase-3/7; furthermore it downregulated the antiapoptotic BCL2 gene and upregulated the proapoptotic BAX gene expression, suggesting that the cause of HeLa cells death might be an increased susceptibility to apoptosis induced by LGI1. The results suggested that LGI1 is capable to restrain growth and survival of adenocarcinoma cells such as HeLa.
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PMID:Expression of LGI1 Impairs Proliferation and Survival of HeLa Cells. 2011 25