DR1-like element in human topoisomerase IIalpha gene involved in enhancement of etoposide-induced apoptosis by PPARgamma ligand.
OBJECTIVE
The nuclear peroxisome proliferator-activated receptor gamma (PPARgamma) ligands may enhance the etoposide-induced apoptosis by modulating the topoisomerase (Topo) IIalpha expression through binding to direct repeat 1 (DR1)-like element.


METHODS
To investigate the effect of etoposide-induced apoptosis by PPARgamma ligands, leukemia cell lines were treated with troglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) in the presence of etoposide and studied about various biological responses.


RESULTS
We found the enhancement of etoposide-induced apoptosis by PPARgamma ligands in several leukemia cell lines, which was dependent on the expression of PPARgamma and specific for TopoIIalpha inhibitor. We also observed the increased expression of TopoIIalpha protein by 15d-PGJ2 in Jurkat and HUVEC cells, which might lead to the increased sensitivity to etoposide. Furthermore, we demonstrated that 15d-PGJ2 enhanced the promoter activity of human TopoIIalpha promoter construct with a DR1-like site by sevenfold when expressed with PPARgamma and RXRalpha. The mutation of DR1-like site decreased the promoter activity, although the direct binding between DR1-like site and PPARgamma/RXRalpha heterodimer was not demonstrated.


CONCLUSIONS
We conclude that the induction of TopoIIalpha expression by PPARgamma ligands via DR1-like site is an important mechanism for the enhancement of etoposide-induced apoptosis and a DR1-like site in TopoIIalpha promoter is involved in transcriptional regulation dependent on PPARgamma ligands and PPARgamma/RXRalpha heterodimer.
Kanbe
Eiki
E
First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan. ekanbe@tsuru.med.nagoya-u.ac.jp
Abe
Akihiro
A
Towatari
Masayuki
M
Kawabe
Tsutomu
T
Saito
Hidehiko
H
Emi
Nobuhiko
N
D000951:Antigens, Neoplasm; D017209:Apoptosis / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000235:genetics*; D004268:DNA-Binding Proteins; D024202:Electrophoretic Mobility Shift Assay; D005047:Etoposide / Q000494:pharmacology*; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia; D008024:Ligands; D016296:Mutagenesis; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000951:Antigens, Neoplasm; D002839:Chromans; D004268:DNA-Binding Proteins; D008024:Ligands; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013844:Thiazoles; D045162:Thiazolidinediones; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; C075995:down-regulator of transcription 1; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; D000077288:Troglitazone; D015230:Prostaglandin D2