Proteasome inhibitors induce peroxisome proliferator-activated receptor transactivation through RXR accumulation and a protein kinase C-dependent pathway.
Peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of nuclear hormone receptors, forms a heterodimeric DNA binding complex with retinoid X receptor (RXR) and serves as a transcriptional regulator of gene expression. In this study, using luciferase assay of a reporter gene containing PPAR response element (PPRE), we found PPRE transactivity was additively induced by PPAR gamma activator (15dPGJ2) and RXR activator (9-cis retinoic acid, 9-cis RA). Proteasome inhibitors MG132 and MG262 also stimulate PPRE transactivity in a concentration-dependent manner, and this effect is synergistic to 15dPGJ2 and 9-cis RA. PKC activation by 12-myristate 13-acetate (PMA) and ingenol 3,20-dibenzoate (IDB) also led to an increased PPRE activation, and this action was additive to PPAR gamma activators and 9-cis RA, but not to proteasome inhibitors. Results indicate that the PPAR gamma enhancing effect of proteasome inhibitors was attributed to redox-sensitive PKC activation. Western blot analysis showed that the protein level of RXR alpha, but not PPAR gamma, RXR beta, or PKC isoforms, was accumulated in the presence of proteasome inhibitors. Taken together, we conclude that proteasome inhibitors can upregulate PPRE activity through RXR alpha accumulation and a PKC-dependent pathway. The former is due to inhibition of RXR alpha degradation through ubiquitin-dependent proteasome system, while the latter is mediated by reactive oxygen species (ROS) production.
Tsao
Wei-Chia
WC
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Wu
Hsiao-Mei
HM
Chi
Kwan-Hwa
KH
Chang
Ying-Hsin
YH
Lin
Wan-Wan
WW
D002460:Cell Line; D006801:Humans; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D011493:Protein Kinase C / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation
D047495:PPAR gamma; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D047490:Retinoid X Receptor alpha; D011493:Protein Kinase C