Cancer cell survival factor LEDGF
/p75 is a nuclear protein that mediates lysosomal stability
Lens Epithelium-Derived Growth Factor (LEDGF/p75) is a member of the hepatoma-derived growth factor family and a transcriptional co-activator and survival factor for lens epithelial cells. The molecular and biological function of the protein is so far poorly described but the majority of mice knockout for LEDGF/p75 dies perinatally with rigorous developmental defects in skeleton formation and hampered locomotor activity signifying an important role in development. We have recently identified LEDGF/p75 as down-regulated in epithelial cancer cells in response to the specific depletion of heat shock protein 70–2 (Hsp70–2) and shown that LEDGF/p75 is a downstream mediator of the cancer cell-selective death induced by Hsp70–2 neutralization. Here we show that LEDGF/p75 is over-expressed in mammary- and bladder cancer biopsies and that it protects cancer cells from an alternative- and caspase-independent apoptosis-like cell death pathway induced by cytotoxic drugs known to compromise lysosomal integrity. The LEDGF/p75 protein is expressed abundantly in all analyzed cancer cell lines and it localizes exclusively to the nucleus where it tightly associates with chromatin throughout the phases of the cell cycle. Contrary to wild type LEDGF/p75, expression of a nuclear localization-deficient mutant of LEDGF/p75 fails to protect the cancer cells from stress-induced cell death. This suggests that LEDGF/p75 mediates cancer-associated lysosomal stability through an indirect mechanism that is unlikely to involve physical interaction with lysosomal components but depends on the nuclear presence of LEDGF/p75.
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Document Type: Abstract
Publication date: May 1, 2008