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Activation of the Nuclear Factor B Pathway by Astrocyte Elevated Gene-1: Implications for Tumor Progression and Metastasis

Departments of ¹ Pathology, ² Urology, and ³ Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York and ⁴ Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia

Requests for reprints: Paul B. Fisher, Department of Pathology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West 168th Street, BB-1501, New York, NY 10032. Phone: 212-305-3642; -3966; Fax: 212-305-8177; E-mail: pbf1{at}columbia.edu.

Astrocyte elevated gene-1 (AEG-1) was initially identified as an HIV-1- and tumor necrosis factor (TNF-)–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 B (NF-B), a TNF- downstream signaling component, is associated with several human illnesses, including cancer, and NF-B 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-B. 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-B. The NF-B activation induced by AEG-1 corresponded with degradation of IB and nuclear translocation of p65 that resulted in the induction of NF-B downstream genes. Infection with an adenovirus expressing the mt32IB superrepressor (Ad.IB-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- 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-B. Our findings suggest that activation of NF-B 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. (Cancer Res 2006; 66(3): 1509-16)

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