Transcription control and neuronal differentiation by agents that activate the LXR nuclear receptor family.
LXR and PPAR receptors belong to the nuclear receptor superfamily of transcriptional activating factors. Using ligand-dependent transcription assays, we found that 5-tetradecyloxy-2-furancarboxylic acid (TOFA) transactivates chimeric receptors composed of the glucocorticoid receptor DNA binding domain and the ligand binding regions of PPARalpha, PPARbeta (NUC-1) and LXRbeta (NER) receptors. In the same assays, ligands for PPARs (oleic acid, WY-14643 and L-631,033) and LXRs (hydroxycholesterols) maintain their respective receptor selectivity. TOFA and hydroxycholesterols also stimulate transcription from a minimal fibrinogen promoter that is under the control of AP-1 or NF-kappaB transcription factor binding sites. In addition to their effects on transcription, these LXRbeta activators induce neuronal differentiation in rat pheochromocytoma cells. TOFA and the natural LXR agonist, 22 (R)-hydroxycholesterol, stimulate neurite outgrowth in 55 and 28% of cells, respectively. No neurite outgrowth was induced by the related 22(S)-hydroxycholesterol, which does not activate the LXR family. These results suggest that the hydroxycholesterol signaling pathway has a complex effect on transcription that mediates the activity of TOFA and hydroxycholesterol on neuronal differentiation in pheochromocytoma cells.
Schmidt
A
A
Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA. schmidta@merck.com
Vogel
R
R
Holloway
M K
MK
Rutledge
S J
SJ
Friedman
O
O
Yang
Z
Z
Rodan
G A
GA
Friedman
E
E
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000494:pharmacology; D004268:DNA-Binding Proteins; D005663:Furans / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D000071518:Liver X Receptors; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D019301:Oleic Acid / Q000494:pharmacology; D057093:Orphan Nuclear Receptors; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D000924:Anticholesteremic Agents; D004268:DNA-Binding Proteins; D005663:Furans; D000960:Hypolipidemic Agents; D000071518:Liver X Receptors; D009414:Nerve Growth Factors; D057093:Orphan Nuclear Receptors; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D019301:Oleic Acid; C014289:5-(tetradecyloxy)-2-furancarboxylic acid; C006253:pirinixic acid; D002784:Cholesterol