Hypoxia-inducible factor 1 (HIF1) is up-regulated in most malignant tumors usually via interruption of ubiquitination and proteasomal degradation of its subunit A. Recently, we have shown that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), activates HIF1A and subsequently expression of HIF1-responsive genes in epithelial cells. Here, we explore the mechanism for HIF1A activation by LMP1 in nasopharyngeal epithelial cells: LMP1 up-regulates the level of Siah1 E3 ubiquitin ligase by enhancing its stability, which subsequently induces proteasomal degradation of prolyl HIF-hydroxylases 1 and 3 that normally mark HIF1A for degradation. As a result, LMP1 prevents formation of von Hippel-Lindau/HIF1A complex, as shown by coimmunoprecipitation analyses. Thus, Siah1 is implicated in the regulation of HIF1A and is involved in a recently appreciated aspect of EBV-mediated tumorigenesis, namely, the angiogenesis process triggered by LMP1. (Cancer Res 2006; 66(20): 9870-7)

The protein levels of ␤-catenin are tightly regulated by the ubiquitin͞proteasome system. We provide evidence that two distinct ubiquitin-dependent degradation pathways for ␤-catenin are active in the same Burkitt's lymphoma cells: Along with the classical glycogen-synthase kinase 3␤-dependent destruction machinery, degradation of ␤-catenin through seven in absentia homolog 1 (Siah-1) ubiquitin ligase is functional in these cells. We show that inhibition of endogenous Siah-1 stabilizes and activates ␤-catenin in B cells. The principal Epstein-Barr virus oncoprotein, latent membrane protein 1, is involved in ␤-catenin up-regulation, and expression of latent membrane protein 1 in B lymphoma cells is associated with decreased Siah-1 RNA and protein levels. Thus, we demonstrate the significance of the endogenous Siah-1-dependent ubiquitin͞proteasome pathway for ␤-catenin degradation in malignant human cells and its regulation by a viral oncogene.B lymphoma ͉ ubiquitin͞proteasomal degradation ͉ Epstein-Barr virus ͉ latent membrane protein 1

The mammalian BAD protein belongs to the BH3-only subgroup of the BCL-2 family. In contrast to its known pro-apoptotic function, we found that endogenous and overexpressed BAD L can inhibit cell death in neurons and other cell types. Several mechanisms regulate the conversion of BAD from an anti-death to a pro-death factor, including alternative splicing that produces the N-terminally truncated BAD S . In addition, caspases convert BAD L into a pro-death fragment that resembles the short splice variant. The caspase site that is selectively cleaved during cell death following growth factor (interleukin-3) withdrawal is conserved between human and murine BAD. A second cleavage site that is required for murine BAD to promote death following Sindbis virus infection, ␥-irradiation, and staurosporine treatment is not conserved in human BAD, consistent with the inability of human BAD to promote death with these stimuli. However, loss of the BAD N terminus by any mechanism is not always sufficient to activate its pro-death activity, suggesting that the N terminus is a regulatory domain rather than an anti-death domain. These findings suggest that BAD is more than an inert death factor in healthy cells; it is also a pro-survival factor, prior to its role in promoting cell death.

No abstract

No abstract