APE1/Ref-1 regulates PTEN expression mediated by Egr-1.
APE1/Ref-1, the mammalian ortholog of E. coli Xth, and a multifunctional protein possessing both DNA repair and transcriptional regulatory activities, has dual role in controlling cellular response to oxidative stress. It is rate-limiting in repair of oxidative DNA damage including strand breaks and also has co-transcriptional activity by modulating genes expression directly regulated by Egr-1 and p53 transcription factors. PTEN, a phosphoinositide phosphatase, acts as an 'off' switch in the PI-3 kinase/Akt signalling pathway and regulates cell growth and survival. It is shown here that transient alteration in the APE1 level in HeLa cells modulates PTEN expression and that acetylatable APE1 is required for the activation of the PTEN gene. Acetylation of APE1 enhances its binding to distinct trans-acting complexes involved in activation or repression. The acetylated protein is deacetylated in vivo by histone deacetylases. It was found that exposure of HeLa cells to H(2)O(2) and to histone deacetylase inhibitors increases acetylation of APE1 and induction of PTEN. The absence of such induction in APE1-downregulated HeLa cells confirmed APE1's role in regulating inducible PTEN expression. That APE1-dependent PTEN expression is mediated by Egr-1 was supported by experiments with cells ectopically expressing Egr-1. Thus, the data open new perspectives in the comprehension of the many functions exerted by APE1 in controlling cell response to oxidative stress.
Fantini
Damiano
D
Department of Biomedical Sciences and Technologies, University of Udine, Udine, Italy.
Vascotto
Carlo
C
Deganuto
Marta
M
Bivi
Nicoletta
N
Gustincich
Stefano
S
Marcon
Gabriella
G
Quadrifoglio
Franco
F
Damante
Giuseppe
G
Bhakat
Kishor K
KK
Mitra
Sankar
S
Tell
Gianluca
G
D000107:Acetylation; D002087:Butyrates / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045325:HCT116 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
D002087:Butyrates; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D006861:Hydrogen Peroxide; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D006655:Histone Deacetylases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase