Synthetic retinoid Am80 inhibits interaction of KLF5 with RAR alpha through inducing KLF5 dephosphorylation mediated by the PI3K/Akt signaling in vascular smooth muscle cells.
Krüppel-like factor 5 (KLF5) is known to physically interact with retinoic acid receptor-alpha (RAR alpha). Here, we show that Am80 inhibited the interaction between KLF5 and RAR alpha and this inhibitory effect was accompanied by the dephosphorylation of KLF5 in VSMCs. Treating VSMCs with LY294002, the PI3K/Akt inhibitor, abrogated Am80-induced KLF5 dephosphorylation and reversed Am80-induced suppression of interaction between KLF5 and RAR alpha, whereas treating vascular smooth muscle cells (VSMCs) with SB203580, the p38 kinase inhibitor, attenuated the interaction between KLF5 and RAR alpha. Constitutively active p38 kinase MKK6b infection prevented the KLF5 dephosphorylation induced by Am80. In conclusion, Am80 induces KLF5 dephosphorylation by activating PI3K/Akt signaling, and inhibits KLF5 phosphorylation by blocking p38 signaling, subsequently leading to the suppression of interaction of KLF5 with RAR alpha.
Zhang
Xin-hua
XH
Department of Biochemistry and Molecular Biology, Hebei Medical University, No. 361, Zhongshan East Road, Shijiazhuang 050017, China.
Zheng
Bin
B
Han
Mei
M
Miao
Sui-bing
SB
Wen
Jin-kun
JK
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047468:Immunoprecipitation; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000494:pharmacology*; D015398:Signal Transduction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D001565:Benzoates; D002867:Chromones; D004791:Enzyme Inhibitors; C492215:Klf5 protein, rat; D051741:Kruppel-Like Transcription Factors; D009025:Morpholines; C000607073:Rara protein, rat; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt