Back to Search
Start Over
Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis.
- Source :
-
Cancer research [Cancer Res] 2006 Feb 01; Vol. 66 (3), pp. 1509-16. - Publication Year :
- 2006
-
Abstract
- Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1- and tumor necrosis factor alpha (TNF-alpha)-inducible transcript in primary human fetal astrocytes by a rapid subtraction hybridization approach. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells and AEG-1 cooperates with Ha-ras to promote transformation of immortalized melanocytes. Activation of the transcription factor nuclear factor kappaB (NF-kappaB), a TNF-alpha downstream signaling component, is associated with several human illnesses, including cancer, and NF-kappaB controls the expression of multiple genes involved in tumor progression and metastasis. We now document that AEG-1 is a significant positive regulator of NF-kappaB. Enhanced expression of AEG-1 via a replication-incompetent adenovirus (Ad.AEG-1) in HeLa cells markedly increased binding of the transcriptional activator p50/p65 complex of NF-kappaB. The NF-kappaB activation induced by AEG-1 corresponded with degradation of IkappaBalpha and nuclear translocation of p65 that resulted in the induction of NF-kappaB downstream genes. Infection with an adenovirus expressing the mt32IkappaBalpha superrepressor (Ad.IkappaBalpha-mt32), which prevents p65 nuclear translocation, inhibited AEG-1-induced enhanced agar cloning efficiency and increased matrigel invasion of HeLa cells. We also document that TNF-alpha treatment resulted in nuclear translocation of both AEG-1 and p65 wherein these two proteins physically interacted, suggesting a potential mechanism by which AEG-1 could activate NF-kappaB. Our findings suggest that activation of NF-kappaB by AEG-1 could represent a key molecular mechanism by which AEG-1 promotes anchorage-independent growth and invasion, two central features of the neoplastic phenotype.
- Subjects :
- Adenoviridae genetics
Amino Acid Sequence
Carrier Proteins antagonists & inhibitors
Carrier Proteins biosynthesis
Carrier Proteins genetics
Cell Adhesion physiology
Cell Adhesion Molecules
Cell Growth Processes physiology
Disease Progression
HeLa Cells
Humans
I-kappa B Proteins metabolism
Interleukin-8 biosynthesis
Interleukin-8 genetics
Membrane Proteins antagonists & inhibitors
Membrane Proteins biosynthesis
Membrane Proteins genetics
Molecular Sequence Data
NF-KappaB Inhibitor alpha
NF-kappa B antagonists & inhibitors
NF-kappa B p50 Subunit metabolism
Protein Binding
RNA, Messenger biosynthesis
RNA, Messenger genetics
RNA-Binding Proteins
Transcription Factor RelA metabolism
Transfection
Up-Regulation
Carrier Proteins physiology
Membrane Proteins physiology
NF-kappa B metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 66
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 16452207
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-05-3029