Focusing on transcription factor families in atherogenesis: the function of LKLF and TR3.
In this overview, two separate studies are discussed that emerged from a "discovery-driven" approach to identify genes that play an essential role in atherogenesis. First, by a combination of DNA micro-array and one-way linkage hierachical clustering, we selected genes that are induced in endothelial cells (EC) by prolonged steady- or pulsatile laminar flow, but of which expression is not affected by inflammatory and mitogenic agents (TGF-beta, IL-1betaTNF-alpha,VEGF, thrombin). The genes selected accordingly were: cytochrome P450 1B1, diaphorase and the transcription factor lung Krüppel-like factor (LKLF) of which only the latter is truly EC specific. LKLF meets the criteria of an anti-atherosclerotic gene, mainly since expression is restricted to areas subjected to laminar flow as shown by in situ hybridization with anatomically well-defined specimens. Second, neointimal (but not medial) smooth muscle cells (SMC) specifically synthesize the NGFI-B subfamily (TR3, MINOR,NOT) of the nuclear hormone superfamily of transcription factors. Again, evidence is presented, indicating that these proteins serve an anti-atherosclerotic function. Notably, transgenic mice, expressing either TR3 or a dominant-negative mutant TR3DeltaTA in arterial SMC, were subjected to carotid artery ligation to induce SMC proliferation. Lesions in TR3-overexpressing transgenic mice were 5-fold smaller than isogenic wild-type mice, while mice overexpressing the TR3DeltaTA mutant had a 3-fold larger lesion. It is proposed that (down-stream products of) TR3 inhibit the cell cycle, since adenovirus-mediated expression of TR3DeltaTA and TR3, respectively, inhibit and promote the synthesis of the cyclin-dependent kinase inhibitor p27(Kip1) in SMC.
Arkenbout
E Karin
EK
Academic Medical Center, Department of Biochemistry (K1-159), Meibergdreef 15, 1105 Amsterdam, The Netherlands.
Dekker
Rob J
RJ
de Vries
Carlie J M
CJ
Horrevoets
Anton J G
AJ
Pannekoek
Hans
H
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009419:Nerve Tissue Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; C490412:NR4A3 protein, human; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D015534:Trans-Activators; D014157:Transcription Factors