#MICHELLE SUBLER ACTIVATOR#
On the other hand it has also been shown that when stimulated by TNFα, an activator of the MAP kinase cascade and NF-κB survival pathways, AEG-1 translocates to the nucleus from the cytoplasm interacting with p65 subunit of NF-κB and CREB-binding protein (CBP), thereby augmenting NF-κB transcriptional activity. It has been suggested that nuclear AEG-1 is a sumoylated protein that undergoes monoubiquitination facilitating its translocation out of the nucleus and increased stability in the cytoplasm. AEG-1 is also detected in the nucleus and nucleolus, mainly in primary cells. In metastatic cancer cells it is also detected in the cell membrane. The predominant intracellular localization of AEG-1 is ER-membrane.
It lacks any other identifiable functional or DNA-binding domains apart from an LXXLL motif present in its N-terminus (21–25 amino acids) with which AEG-1 interacts with the transcription factor Retinoid X Receptor (RXR) negatively regulating its activity. AEG-1 protein contains 582 amino acids rich in lysines, with a 50–77 amino acids single-pass transmembrane domain (TMD) and multiple nuclear localization signals (NLS) ( Figure 1). The AEG-1 locus is present on human chromosome 8q22 and contains 12 exons and 11 introns. In this review a comprehensive analysis of the current and up-to-date literature is provided to delineate the clinical significance of AEG-1 in cancer highlighting the commonality of the findings and the discrepancies and discussing the implications of these observations. Additionally, clinicopathologic correlations of AEG-1 expression in a diverse array of cancers establishing AEG-1 as an independent biomarker for highly aggressive, chemoresistance metastatic disease with poor prognosis have provided a solid foundation to the mechanistic and mouse model studies.
These findings have been strongly buttressed by demonstration of increased tumorigenesis in tissue-specific AEG-1 transgenic mouse models, and profound resistance of multiple types of cancer development and progression in total and conditional AEG-1 knockout mouse models. In all types of cancer cells, overexpression and knockdown studies have demonstrated that AEG-1 performs a seminal role in regulating proliferation, invasion, angiogenesis, metastasis and chemoresistance, the defining cancer hallmarks, by a variety of mechanisms, including protein-protein interactions activating diverse oncogenic pathways, RNA-binding promoting translation and regulation of inflammation, lipid metabolism and tumor microenvironment. Since its initial cloning in 2002, a plethora of studies in a vast number of cancer indications, has strongly established AEG-1 as a bona fide oncogene.
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