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PMID:18316612

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Citation

Sarkar, D, Park, ES, Emdad, L, Lee, SG, Su, ZZ and Fisher, PB (2008) Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res. 68:1478-84

Abstract

Malignant glioma is a consistently fatal brain cancer. The tumor invades the surrounding tissue, limiting complete surgical removal and thereby initiating recurrence. Identifying molecules critical for glioma invasion is essential to develop targeted, effective therapies. The expression of astrocyte elevated gene-1 (AEG-1) increases in malignant glioma and AEG-1 regulates in vitro invasion and migration of malignant glioma cells by activating the nuclear factor-kappaB (NF-kappaB) signaling pathway. The present studies elucidate the domains of AEG-1 important for mediating its function. Serial NH(2)-terminal and COOH-terminal deletion mutants were constructed and functional analysis revealed that the NH(2)-terminal 71 amino acids were essential for invasion, migration, and NF-kappaB-activating properties of AEG-1. The p65-interaction domain was identified between amino acids 101 to 205, indicating that p65 interaction alone is not sufficient to mediate AEG-1 function. Coimmunoprecipitation assays revealed that AEG-1 interacts with cyclic AMP-responsive element binding protein-binding protein (CBP), indicating that it might act as a bridging factor between NF-kappaB, CBP, and the basal transcription machinery. Chromatin immunoprecipitation assays showed that AEG-1 is associated with the NF-kappaB binding element in the interleukin-8 promoter. Thus, AEG-1 might function as a coactivator for NF-kappaB, consequently augmenting expression of genes necessary for invasion of glioma cells. In these contexts, AEG-1 represents a viable potential target for the therapy of malignant glioma.

Links

PubMed Online version:10.1158/0008-5472.CAN-07-6164

Keywords

Brain Neoplasms/metabolism; CREB-Binding Protein/metabolism; Cell Adhesion Molecules/biosynthesis; Cell Line, Tumor; Cell Movement; Cell Nucleus/metabolism; Gene Expression Regulation, Neoplastic; Glioma/metabolism; Humans; Membrane Proteins/biosynthesis; Models, Biological; NF-kappa B/genetics; NF-kappa B/metabolism; Neoplasm Invasiveness; Promoter Regions, Genetic; Protein Binding; Transcription, Genetic

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CREB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q86UE4

F

Seeded From UniProt

complete

HUMAN:LYRIC

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92793

F

Seeded From UniProt

complete

HUMAN:LYRIC

enables

GO:0061629: RNA polymerase II-specific DNA-binding transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P16220

F

Seeded From UniProt

complete

HUMAN:CBP

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q86UE4

F

Seeded From UniProt

complete

HUMAN:LYRIC

involved_in

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LYRIC

involved_in

GO:0051092: positive regulation of NF-kappaB transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LYRIC

enables

GO:0001085: RNA polymerase II transcription factor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P16220

F

Seeded From UniProt

complete

HUMAN:LYRIC

enables

GO:0003713: transcription coactivator activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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