Angiotensin II stimulates KLF5 phosphorylation and its interaction with c-Jun leading to suppression of p21 expression in vascular smooth muscle cells.
Krüppel-like factor 5 (KLF5) and c-Jun are involved in angiotensin II (Ang II)-induced cell proliferation and play an important role in p21 expression. But the direct and functional implications of KLF5 and c-Jun in regulating p21 expression in vascular smooth muscle cells (VSMCs) are unclear. Here, we show that Ang II upregulated KLF5 and c-Jun expression and inhibited p21 expression in VSMCs, and silencing of KLF5 expression by KLF5-specific small interfering RNA (siRNA) neutralized the inhibitory effects of Ang II on p21 expression. Exposure of VSMCs to Ang II rapidly and strongly stimulated KLF5 phosphorylation, which results in an increase of the interaction of KLF5 with c-Jun. Treating VSMCs with PD98059, the ERK inhibitor, inhibited ERK activation and KLF5 phosphorylation as well as the interaction between KLF5 and c-Jun. Reporter analysis showed that both KLF5 and c-Jun cooperatively repressed the promoter of p21. Furthermore, KLF5 bound to its cis-elements in the p21 promoter, and meanwhile interacted with c-Jun in Ang II-induced VSMCs. These results suggest that Ang II induces KLF5 phosphorylation mediated by the ERK signalling in VSMCs, which in turn stimulates the interaction of KLF5 with c-Jun, subsequently leads to the suppression of p21 expression.
He
Ming
M
Department of Biochemistry, Hebei Medical University, No. 361, Zhongshan East Road, Shijiazhuang 050017, China.
Han
Mei
M
Zheng
Bin
B
Shu
Ya-Nan
YN
Wen
Jin-Kun
JK
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D050759:Cyclin-Dependent Kinase Inhibitor p21; D005419:Flavonoids; C492215:Klf5 protein, rat; D051741:Kruppel-Like Transcription Factors; D016755:Proto-Oncogene Proteins c-jun; D000804:Angiotensin II; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one