The
lens epithelium-derived growth factor p75 (
LEDGF/p75) is a transcription coactivator that promotes resistance to oxidative stress- and
chemotherapy-induced cell death.
LEDGF/p75 is also known as the dense fine speckles
autoantigen of 70 kDa (DFS70) and has been implicated in
cancer, HIV-
AIDS, autoimmunity, and
inflammation. To gain insights into mechanisms by which
LEDGF/p75 protects
cancer cells against stress, we initiated an analysis of its interactions with other
transcription factors and the influence of these interactions on stress gene activation. We report here that both
LEDGF/p75 and its short splice variant
LEDGF/p52 interact with MeCP2, a methylation-associated transcriptional modulator, in vitro and in various human
cancer cells. These interactions were established by several complementary approaches:
transcription factor protein arrays, pull-down and AlphaScreen assays, coimmunoprecipitation, and nuclear colocalization by confocal microscopy. MeCP2 was found to interact with the N-terminal region shared by
LEDGF/p75 and p52, particularly with the PWWP-CR1 domain. Like
LEDGF/p75, MeCP2 bound to and transactivated the Hsp27 promoter (Hsp27pr).
LEDGF/p75 modestly enhanced MeCP2-induced Hsp27pr transactivation in U2OS
osteosarcoma cells, whereas this effect was more pronounced in PC3
prostate cancer cells.
LEDGF/p52 repressed Hsp27pr activity in U2OS cells. Interestingly,
siRNA-induced silencing of
LEDGF/p75 in U2OS cells dramatically elevated MeCP2-mediated Hsp27pr transactivation, whereas this effect was less pronounced in PC3 cells depleted of
LEDGF/p75. These results suggest that the
LEDGF/p75-MeCP2 interaction differentially influences Hsp27pr activation depending on the cellular and molecular context. These findings are of significance in understanding the contribution of this interaction to the activation of stress survival genes.