RGD Reference Report - Kruppel-like factor 4 inhibits proliferation by platelet-derived growth factor receptor beta-mediated, not by retinoic acid receptor alpha-mediated, phosphatidylinositol 3-kinase and ERK signaling in vascular smooth muscle cells.

General

Kruppel-like factor 4 inhibits proliferation by platelet-derived growth factor receptor beta-mediated, not by retinoic acid receptor alpha-mediated, phosphatidylinositol 3-kinase and ERK signaling in vascular smooth muscle cells.
Authors:	Zheng, B Han, M Bernier, M Zhang, XH Meng, F Miao, SB He, M Zhao, XM Wen, JK
Citation:	Zheng B, etal., J Biol Chem. 2009 Aug 21;284(34):22773-85. doi: 10.1074/jbc.M109.026989. Epub 2009 Jun 16.
RGD ID:	8553301
Pubmed:	PMID:19531492 (View Abstract at PubMed)
PMCID:	PMC2755685 (View Article at PubMed Central)
DOI:	DOI:10.1074/jbc.M109.026989 (Journal Full-text)
Proliferation inhibition of vascular smooth muscle cells (VSMCs) is governed by the activity of a transcription factor network. Kruppel-like factor 4 (Klf4), retinoic acid receptor (RAR alpha), and platelet-derived growth factor receptor (PDGFR) are expressed in VSMCs and are components of such a network. However, the relationship among them in the regulation of VSMC proliferation remains unknown. Here, we investigated the mechanisms whereby Klf4 mediates the growth inhibitory effects in VSMCs through RAR alpha and PDGFR beta. We demonstrated that Klf4 directly binds to the 5' regulatory region of RAR alpha, down-regulates RAR alpha expression, and specifically inhibits RAR alpha-mediated phosphatidylinositol 3-kinase (PI3K) and ERK signaling in cultured VSMCs induced by the synthetic retinoid Am80. Of particular interest, Klf4 inhibits RAR alpha and PDGFR beta expression while blocking PI3K and ERK signaling induced by Am80 and PDGF-BB, respectively. The anti-proliferative effects of Klf4 on neointimal formation depend largely on PDGFR-mediated PI3K signaling without involvement of the RAR alpha-activated signaling pathways. These findings provide a novel mechanism for signal suppression and growth inhibitory effects of Klf4 in VSMCs. Moreover, the results of this study suggest that Klf4 is one of the key mediators of retinoid actions in VSMCs.

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Biological Process

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
negative regulation of DNA-templated transcription	involved_in	IMP		8553301	PMID:19531492	UniProt
negative regulation of ERK1 and ERK2 cascade	involved_in	IMP		8553301	PMID:19531492	UniProt
negative regulation of muscle hyperplasia	involved_in	IMP		8553301	PMID:19531492	UniProt
negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	involved_in	IMP		8553301	PMID:19531492	UniProt
negative regulation of smooth muscle cell proliferation	involved_in	IMP		8553301	PMID:19531492	UniProt

Molecular Function

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
phosphatidylinositol 3-kinase regulator activity	enables	IMP		8553301	PMID:19531492	UniProt
transcription cis-regulatory region binding	enables	IDA		8553301	PMID:19531492	UniProt

Objects Annotated

Genes (Rattus norvegicus)

Klf4 (KLF transcription factor 4)

Objects referenced in this article

Gene	Rara	retinoic acid receptor, alpha	Rattus norvegicus

Additional Information

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Kruppel-like factor 4 inhibits proliferation by platelet-derived growth factor receptor beta-mediated, not by retinoic acid receptor alpha-mediated, phosphatidylinositol 3-kinase and ERK signaling in vascular smooth muscle cells.