Expression of a defective mouse mammary tumor virus envelope glycoprotein precursor which binds stably to GRP78 within the lumen of the endoplasmic reticulum is associated with decreased glucocorticoid-induced apoptosis in mouse lymphoma cells

Abstract

Viral proteins inhibit apoptosis in host cells by a variety of mechanisms. This report proposes an additional mechanism, based on the interaction of a mutant mouse mammary tumor virus (MMTV) envelope glycoprotein precursor, Pr74, with the stress protein GRP78 (BiP) within the lumen of the endoplasmic reticulum (ER) (J. Biol. Chem. 268 7482 ± 7488, 1993). We show that WEHI7.2 (W7.2) mouse lymphoma cells, which do not express Pr74, are more sensitive to cell death induction by the glucocorticoid hormone dexamethasone (dex), than W7MG1 cells, which were derived by infecting W7.2 cells with MMTV and therefore express Pr74 under control of the glucocorticoid-inducible MMTV promoter. Moreover, W7-ENV/N cells, derived by stably transfecting W7.2 cells with a constitutively expressed cDNA encoding mutant Pr74, were less sensitive to dex-induced cell death than control transfectant W7-ENV/7 cells. Among multiple W7-ENV/N subclones, susceptibility to dex-induced cell death was inversely related to the level of Pr74 synthesis. The interaction of Pr74 with GRP78 induces an increase in GRP78 synthesis. Thus, the repression of cell death associated with Pr74 expression may be secondary to elevated synthesis of GRP78, a stress protein previously implicated in protection against cell death.

GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer

“…In this study, overexpression of one or more of the GAS5 ESTs induced or facilitated apoptosis in all the cell lines examined. In the mouse thymoma W7.2c and the breast epithelial MCF-10A cell lines, overexpression of GAS5 did not induce growth arrest by itself, but did produce a clear increase in sensitivity to treatments that induce apoptosis by several different pathways (Fan et al, 1995;Lam et al, 1997;Rossini et al, 2001; Mourtada-Maarabouni et al, 2003a; Thomadaki and Scorilas, 2007). For the breast epithelial MCF-7 and HEK 293T cell lines, overexpression of some GAS5 ESTs induced apoptosis without any additional stimulus (Figures 4b and 5a).…”