Transcriptional induction of mitogen-activated protein kinase phosphatase 1 by retinoids. Selective roles of nuclear receptors and contribution to the antiapoptotic effect.
All-trans-retinoic acid (t-RA) inhibits hydrogen peroxide (H(2)O(2))-induced apoptosis by inhibiting the c-Jun N-terminal kinase (JNK)-activator protein 1 (AP-1) pathway. In this report, we examined the involvement of mitogen-activated protein kinase phosphatase 1 (MKP-1) in suppression of JNK and the antiapoptotic effect of t-RA and the roles of nuclear receptors in the regulation of MKP-1 by t-RA. We found that not only t-RA, but also a selective agonist of retinoic acid receptor (RAR), a selective agonist of retinoid X receptor (RXR), and a pan-agonist of RAR and RXR all induced MKP-1 at the transcriptional level. Activation of RAR was required for all of these triggering effects, but activation of RXR was required only for the RXR agonist-induced MKP-1 expression. Among the three RAR subtypes, RARalpha and RARgamma, but not RARbeta, mediated the t-RA-induced MKP-1 expression. The antiapoptotic effect of t-RA on H(2)O(2)-induced apoptosis in several cell types was correlated with the inducibility of MKP-1 by t-RA. Inhibition of MKP-1 by vanadate enhanced JNK phosphorylation and attenuated the antiapoptotic effect of t-RA. Furthermore, overexpression of MKP-1 inhibited H(2)O(2)-induced JNK phosphorylation and apoptosis. To our knowledge, this is the first to demonstrate that 1) MKP-1 is inducible by retinoids at the transcriptional level, 2) RXR and individual RAR subtypes have different roles in this process, and 3) the induced MKP-1 plays a significant role in mediating both JNK inhibition and the antiapoptotic effect of t-RA in oxidative stress.
Department of Medicine, Royal Free and University College Medical School, University College London, United Kingdom. q.xu@ucl.ac.uk
Qihe
Q
Xu
Tsuneo
T
Konta
Akira
A
Furusu
Kenji
K
Nakayama
Javier
J
Lucio-Cazana
Leon G
LG
Fine
Masanori
M
Kitamura
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D004790:Enzyme Induction; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D006861:Hydrogen Peroxide; D017874:Immediate-Early Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607073:Rara protein, rat; C517021:Dusp1 protein, rat