PPARgamma ligands suppress the feedback loop between E2F2 and cyclin-E1.
PPARgamma is a nuclear hormone receptor that plays a key role in the induction of peroxisome proliferation. A number of studies showed that PPARgamma ligands suppress cell cycle progression; however, the mechanism remains to be determined. Here, we showed that PPARgamma ligand troglitazone inhibited G1/S transition in colon cancer cells, LS174T. Troglitazone did not affect on either expression of CDK inhibitor (p18) or Wnt signaling pathway, indicating that these pathways were not involved in the troglitazone-dependent cell cycle arrest. GeneChip and RT-PCR analyses revealed that troglitazone decreased mRNA levels of cell cycle regulatory factors E2F2 and cyclin-E1 whose expression is activated by E2F2. Down-regulation of E2F2 by troglitazone results in decrease of cyclin-E1 transcription, which could inhibit phosphorylation of Rb protein, and consequently evoke the suppression of E2F2 transcriptional activity. Thus, we propose that troglitazone suppresses the feedback loop containing E2F2, cyclin-E1, and Rb protein.
Komatsu
Yoko
Y
Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki 305-8572, Japan.
Ito
Ichiaki
I
Wayama
Mitsutoshi
M
Fujimura
Akiko
A
Akaogi
Kensuke
K
Machida
Hikaru
H
Nakajima
Yuka
Y
Kuroda
Takao
T
Ohmori
Kazuji
K
Murayama
Akiko
A
Kimura
Keiji
K
Yanagisawa
Junn
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000378:metabolism*; D019927:Cyclin E / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050703:E2F2 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D000077288:Troglitazone; D051153:Wnt Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; C475820:CCNE1 protein, human; D002839:Chromans; D019927:Cyclin E; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; D008024:Ligands; D015513:Oncogene Proteins; D047495:PPAR gamma; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D045162:Thiazolidinediones; D051153:Wnt Proteins; D000077288:Troglitazone