Non-sterol regulation of low density lipoprotein receptor gene expression in T cells.
Non-sterol regulation of low density lipoprotein (LDL) receptor gene expression was examined in a mitogen-responsive human T cell line. Stimulation of the leukemic T cell line Jurkat with the phorbol ester phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin rapidly and transiently increased LDL receptor mRNA levels. Inhibition of protein synthesis with cycloheximide (CHX) or puromycin resulted in superinduction of LDL receptor mRNA levels by mitogenic stimulation. The increase in LDL receptor mRNA levels resulted from increased gene transcription rather than stabilization of mRNA half-life. Thus, similar results were obtained when reporter gene expression was assessed in Jurkat cells transfected with LDL receptor promoter constructs and mRNA half-life was not significantly altered by the stimuli. Neither mitogenic induction nor superinduction of LDL receptor mRNA levels in Jurkat cells was prevented by sterol downregulation of LDL receptor gene expression. The protein synthesis inhibitors CHX and anisomycin, but not puromycin, also directly stimulated LDL receptor mRNA levels, suggesting that these compounds could provide a signal required for LDL receptor gene transcription. Taken together, these data indicate that various non-sterol stimuli, including activation of protein kinase C, increases in intracellular calcium, inhibition of protein synthesis, and signals generated by the protein synthesis inhibitors CHX and anisomycin, induce LDL receptor gene expression. Thus, transcription of the LDL receptor gene is not only regulated by ambient sterols but also by a variety of influences that govern the various primary response or immediate early genes. These stimuli may play an important role in normal regulation of LDL receptor gene expression.
Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas 75235-8887.
R S
RS
Makar
P E
PE
Lipsky
J A
JA
Cuthbert
D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D015458:Leukemia, T-Cell / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology*; D011973:Receptors, LDL / Q000235:genetics*; D013261:Sterols; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D008934:Mitogens; D011973:Receptors, LDL; D013261:Sterols; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate