Alternative Splicing and Caspase-Mediated Cleavage Generate Antagonistic Variants of the Stress Oncoprotein LEDGF/p75

Abstract

There is increasing evidence that an augmented state of cellular oxidative stress modulates the expression of stress genes implicated in diseases associated with health disparities such as certain cancers and diabetes. Lens epithelium -derived growth factor p75 (LEDGF/ p75), also known as DFS70 autoantigen, is emerging as a survival oncoprotein that promotes resistance to oxidative stress -induced cell death and chemotherapy. We previously showed that LEDGF/p75 is targeted by autoantibodies in prostate cancer patients and is overexpressed in prostate tumors, and that its stress survival activity is abrogated during apoptosis. LEDGF/ p75 has a COOH-terminally truncated splice variant, p52, whose role in stress survival and apoptosis has not been thoroughly investigated. We observed unbalanced expression of these proteins in a panel of tumor cell lines, with LEDGF/p75 generally expressed at higher levels. During apoptosis, caspase-3 cleaved p52 to generate a p38 fragment that lacked the NH 2 -terminal PWWP domain and failed to transactivate the Hsp27 promoter in reporter assays. However, p38 retained chromatin association properties and repressed the transactivation potential of LEDGF/p75. Overexpression of p52 or its variants with truncated PWWP domains in several tumor cell lines induced apoptosis, an activity that was linked to the presence of an intron-derived COOH-terminal sequence. These results implicate the PWWP domain of p52 in transcription function but not in chromatin association and proapoptotic activities. Consistent with their unbalanced expression in tumor cells, LEDGF/p75 and p52 seem to play antagonistic roles in the cellular stress response and could serve as targets for novel antitumor therapies.

JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma

“…LEDGF/p75 is a potent oncogene with known diverse functions in cell survival, chemotherapy resistance, tumor progression (41,48,49), and leukemic transformation via interactions with MLL oncoproteins (30). Although our studies indicated a tight convergence of LEDGF/p75 and JPO2 on promigratory AKT signaling, we observed that JPO2 and LEDGF/p75 did not always have overlapping cellular and signaling effects in UW228 and UW426 medulloblastoma cell lines.…”

LEDGF/p75 TATA-Less Promoter Is Driven by the Transcription Factor Sp1

“…Apart from its co-activator role, little is known about p52 1 . Recent findings suggested that p52 overexpression was able to promote apoptosis in cancer cells 5 , and to favor neurite growth and axonal elongation in neural cells 6 .…”

“…Recently, Brown-Bryan et al showed that LEDGF/p75 and its shorter splice variant p52 are overexpressed, in tumor cells 5 . It has been…”

“…The opposite effect has been observed in transforming growth factor β (TGF-β)-treated cells reducing LEDGF/p75 mRNA expression and stress-related LEDGF/p75 downstream genes 31 . In contrast to LEDGF/p75, overexpression of p52 induced apoptosis, and caspasemediated cleavage of p52 generates a shorter fragment that interferes with the transactivation potential of the survival LEDGF/p75 protein in various tumor cell lines 5 . Understanding expression of PSIP1 splice variants may help modulating the fate of cancer cells, either survival or death, and therefore may provide attractive strategies to overcome tumor chemoresistance as well as reducing the tumorigenic potential of LEDGF/p75-overexpressing cells 10; 11; 32 .…”

Differential response of gastric carcinoma MKN-45 and 23132/87 cells to H2O2 exposure

“…Oxidative stress results when the balance between the production of ROS overrides the antioxidant capability of the target cell; oxidative damage from the interaction of reactive oxygen with critical cellular macromolecules may occur (2). It may play a role in carcinogenesis through its numerous effects on the cells, including damage to protein and lipid, and DNA consequently changes in membrane structure and function (3)(4)(5) and gene expression (6)(7)(8). This in turn leads to alterations in cell turnover and enhanced cell death, and subsequently, the accumulation of oxidative damage causes formation of cancer (9).…”