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. 1989 Jun;9(6):2298–2302. doi: 10.1128/mcb.9.6.2298

Involvement of second messengers in regulation of the low-density lipoprotein receptor gene.

J H Auwerx 1, A Chait 1, G Wolfbauer 1, S S Deeb 1
PMCID: PMC362302  PMID: 2548077

Abstract

Transcription of the low-density lipoprotein receptor (LDL-R) gene in the human monocytic leukemic cell line THP-1 and in the human hepatocarcinoma cell line Hep-G2 is regulated by second messengers of the diacylglycerol-protein kinase C (DAG-PKC), inositol 1,4,5-triphosphate-Ca2+, and cyclic AMP pathways. Exogenous phospholipase C (which releases DAG and inositol 1,4,5-triphosphate), PKC activators (phorbol esters and DAG), Ca2+ ionophores, and a cyclic AMP analog all transiently induced accumulation of LDL-R mRNA. The effects of these three signal-transducing pathways were to a large extent additive. Furthermore, PKC stimulation effected an increase in LDL binding, which suggested that the increase in LDL-R mRNA resulted in an increase in functional cell surface receptor activity. These results suggest that uptake of cholesterol by these cells is under control of both intracellular cholesterol levels and external signals.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auwerx J. H., Chait A., Deeb S. S. Regulation of the low density lipoprotein receptor and hydroxymethylglutaryl coenzyme A reductase genes by protein kinase C and a putative negative regulatory protein. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1133–1137. doi: 10.1073/pnas.86.4.1133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Auwerx J. H., Deeb S., Brunzell J. D., Peng R., Chait A. Transcriptional activation of the lipoprotein lipase and apolipoprotein E genes accompanies differentiation in some human macrophage-like cell lines. Biochemistry. 1988 Apr 19;27(8):2651–2655. doi: 10.1021/bi00408a003. [DOI] [PubMed] [Google Scholar]
  3. Bachs O., Carafoli E. Calmodulin and calmodulin-binding proteins in liver cell nuclei. J Biol Chem. 1987 Aug 5;262(22):10786–10790. [PubMed] [Google Scholar]
  4. Bell R. M. Protein kinase C activation by diacylglycerol second messengers. Cell. 1986 Jun 6;45(5):631–632. doi: 10.1016/0092-8674(86)90774-9. [DOI] [PubMed] [Google Scholar]
  5. Bravo R., Neuberg M., Burckhardt J., Almendral J., Wallich R., Müller R. Involvement of common and cell type-specific pathways in c-fos gene control: stable induction of cAMP in macrophages. Cell. 1987 Jan 30;48(2):251–260. doi: 10.1016/0092-8674(87)90428-4. [DOI] [PubMed] [Google Scholar]
  6. Cambier J. C., Newell M. K., Justement L. B., McGuire J. C., Leach K. L., Chen Z. Z. Ia binding ligands and cAMP stimulate nuclear translocation of PKC in B lymphocytes. Nature. 1987 Jun 18;327(6123):629–632. doi: 10.1038/327629a0. [DOI] [PubMed] [Google Scholar]
  7. Chait A., Ross R., Albers J. J., Bierman E. L. Platelet-derived growth factor stimulates activity of low density lipoprotein receptors. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4084–4088. doi: 10.1073/pnas.77.7.4084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Cleveland D. W., Lopata M. A., MacDonald R. J., Cowan N. J., Rutter W. J., Kirschner M. W. Number and evolutionary conservation of alpha- and beta-tubulin and cytoplasmic beta- and gamma-actin genes using specific cloned cDNA probes. Cell. 1980 May;20(1):95–105. doi: 10.1016/0092-8674(80)90238-x. [DOI] [PubMed] [Google Scholar]
  11. Fisch T. M., Prywes R., Roeder R. G. c-fos sequence necessary for basal expression and induction by epidermal growth factor, 12-O-tetradecanoyl phorbol-13-acetate and the calcium ionophore. Mol Cell Biol. 1987 Oct;7(10):3490–3502. doi: 10.1128/mcb.7.10.3490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Goldstein J. L., Basu S. K., Brunschede G. Y., Brown M. S. Release of low density lipoprotein from its cell surface receptor by sulfated glycosaminoglycans. Cell. 1976 Jan;7(1):85–95. doi: 10.1016/0092-8674(76)90258-0. [DOI] [PubMed] [Google Scholar]
  13. Goldstein J. L., Brown M. S. Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasma cholesterol. J Lipid Res. 1984 Dec 15;25(13):1450–1461. [PubMed] [Google Scholar]
  14. Heinecke J. W., Rosen H., Suzuki L. A., Chait A. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem. 1987 Jul 25;262(21):10098–10103. [PubMed] [Google Scholar]
  15. Hokin L. E. Receptors and phosphoinositide-generated second messengers. Annu Rev Biochem. 1985;54:205–235. doi: 10.1146/annurev.bi.54.070185.001225. [DOI] [PubMed] [Google Scholar]
  16. Imagawa M., Chiu R., Karin M. Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP. Cell. 1987 Oct 23;51(2):251–260. doi: 10.1016/0092-8674(87)90152-8. [DOI] [PubMed] [Google Scholar]
  17. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  18. Lehrach H., Diamond D., Wozney J. M., Boedtker H. RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochemistry. 1977 Oct 18;16(21):4743–4751. doi: 10.1021/bi00640a033. [DOI] [PubMed] [Google Scholar]
  19. Lindsten T., June C. H., Thompson C. B. Multiple mechanisms regulate c-myc gene expression during normal T cell activation. EMBO J. 1988 Sep;7(9):2787–2794. doi: 10.1002/j.1460-2075.1988.tb03133.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Means A. R., Tash J. S., Chafouleas J. G. Physiological implications of the presence, distribution, and regulation of calmodulin in eukaryotic cells. Physiol Rev. 1982 Jan;62(1):1–39. doi: 10.1152/physrev.1982.62.1.1. [DOI] [PubMed] [Google Scholar]
  21. Nevins J. R. Isolation and analysis of nuclear RNA. Methods Enzymol. 1987;152:234–241. doi: 10.1016/0076-6879(87)52025-0. [DOI] [PubMed] [Google Scholar]
  22. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  23. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  24. Roesler W. J., Vandenbark G. R., Hanson R. W. Cyclic AMP and the induction of eukaryotic gene transcription. J Biol Chem. 1988 Jul 5;263(19):9063–9066. [PubMed] [Google Scholar]
  25. Rozengurt E. Early signals in the mitogenic response. Science. 1986 Oct 10;234(4773):161–166. doi: 10.1126/science.3018928. [DOI] [PubMed] [Google Scholar]
  26. Russell D. W., Yamamoto T., Schneider W. J., Slaughter C. J., Brown M. S., Goldstein J. L. cDNA cloning of the bovine low density lipoprotein receptor: feedback regulation of a receptor mRNA. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7501–7505. doi: 10.1073/pnas.80.24.7501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sheng M., Dougan S. T., McFadden G., Greenberg M. E. Calcium and growth factor pathways of c-fos transcriptional activation require distinct upstream regulatory sequences. Mol Cell Biol. 1988 Jul;8(7):2787–2796. doi: 10.1128/mcb.8.7.2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shibanuma M., Kuroki T., Nose K. Inhibition of proto-oncogene c-fos transcription by inhibitors of protein kinase C and ion transport. Eur J Biochem. 1987 Apr 1;164(1):15–19. doi: 10.1111/j.1432-1033.1987.tb10985.x. [DOI] [PubMed] [Google Scholar]
  29. Stout R. W., Bierman E. L. Dibutyryl cyclic AMP inhibits LDL binding in cultured fibroblasts and arterial smooth muscle cells. Atherosclerosis. 1983 Jan;46(1):13–20. doi: 10.1016/0021-9150(83)90159-4. [DOI] [PubMed] [Google Scholar]
  30. Tsuchiya S., Yamabe M., Yamaguchi Y., Kobayashi Y., Konno T., Tada K. Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer. 1980 Aug;26(2):171–176. doi: 10.1002/ijc.2910260208. [DOI] [PubMed] [Google Scholar]
  31. Verma I. M., Sassone-Corsi P. Proto-oncogene fos: complex but versatile regulation. Cell. 1987 Nov 20;51(4):513–514. doi: 10.1016/0092-8674(87)90115-2. [DOI] [PubMed] [Google Scholar]
  32. Yamamoto K. K., Gonzalez G. A., Biggs W. H., 3rd, Montminy M. R. Phosphorylation-induced binding and transcriptional efficacy of nuclear factor CREB. Nature. 1988 Aug 11;334(6182):494–498. doi: 10.1038/334494a0. [DOI] [PubMed] [Google Scholar]
  33. Yamamoto T., Davis C. G., Brown M. S., Schneider W. J., Casey M. L., Goldstein J. L., Russell D. W. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell. 1984 Nov;39(1):27–38. doi: 10.1016/0092-8674(84)90188-0. [DOI] [PubMed] [Google Scholar]
  34. Yoshimasa T., Sibley D. R., Bouvier M., Lefkowitz R. J., Caron M. G. Cross-talk between cellular signalling pathways suggested by phorbol-ester-induced adenylate cyclase phosphorylation. Nature. 1987 May 7;327(6117):67–70. doi: 10.1038/327067a0. [DOI] [PubMed] [Google Scholar]

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