Title: The stress oncoprotein LEDGF/p75 interacts with the methyl CpG binding protein MeCP2 and influences its transcriptional activity
Authors: Leoh, Lai Sum
van Heertum, Bart
De Rijck, Jan
Filippova, Maria
Rios-Colon, Leslimar
Basu, Anamika
Martinez, Shannalee R
Tungteakkhun, Sandy S
Filippov, Valeri
Christ, Frauke
De Leon, Marino
Debyser, Zeger
Casiano, Carlos A # ×
Issue Date: Jan-2012
Publisher: American Association for Cancer Research
Series Title: Molecular Cancer Research vol:10 issue:3 pages:378-391
Abstract: The lens epithelium derived growth factor p75 (LEDGF/p75) is a transcription co-activator that promotes resistance to oxidative stress- and chemotherapy-induced cell death. LEDGF/p75 is also known as the dense fine speckles autoantigen of 70 kD (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, co-immunoprecipitation, and nuclear co-localization 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 cells, while this effect was more pronounced in PC3 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.
ISSN: 1541-7786
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
× corresponding author
# (joint) last author

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