Abstract
In different experimental models, retinoid has been shown to stimulate or suppress mitogenesis in cultured cells. The mechanisms underlying this seemingly paradoxical activity remain only partially understood. We have examined the ability of all-trans retinoic acid (ATRA), as well as a number of synthetic retinoids, either alone or in the presence of a mitogenic stimulus (i.e., endothelin), to regulate DNA synthesis and cell replication in cultured rat aortic smooth muscle cells. ATRA alone stimulates [3H]thymidine incorporation (approximately twofold) and increases cell number (approximately twofold) in these cultures but suppresses [3H]thymidine incorporation and reduces cell number in cultures treated with endothelin. The reduction in endothelin-stimulated DNA synthesis correlates closely with the ability of ATRA to inhibit endothelin-stimulated extracellular signal-regulated kinase but not c-Jun NH2-terminal kinase activity. Activation of mitogenesis, seen in the presence of ATRA alone, was independent of extracellular signal-regulated kinase activation but correlated well with increased expression of cyclin D1 mRNA and protein. Concomitant activation of the cdk inhibitor p21 led to truncation of ATRA's mitogenic activity at higher doses of ligand. Collectively, these data indicate that the role of retinoids in the regulation of mitogenesis in vascular smooth muscle is complex. Under quiescent conditions they activate mitogenesis, while in the presence of growth stimulation, as is frequently seen with vasculopathic conditions, they suppress mitogenesis. It appears that independent circuitry is involved in signaling each of these effects.
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- Babajko S., Binoux M. Modulation by retinoic acid of insulin-like growth factor (IGF) and IGF binding protein expression in human SK-N-SH neuroblastoma cells. Eur J Endocrinol. 1996 Apr;134(4):474–480. doi: 10.1530/eje.0.1340474. [DOI] [PubMed] [Google Scholar]
- Bauer R. F., Arthur L. O., Fine D. L. Propagation of mouse mammary tumor cell lines and production of mouse mammary tumor virus in a serum-free medium. In Vitro. 1976 Aug;12(8):558–563. doi: 10.1007/BF02797439. [DOI] [PubMed] [Google Scholar]
- Cadwallader K., Beltman J., McCormick F., Cook S. Differential regulation of extracellular signal-regulated protein kinase 1 and Jun N-terminal kinase 1 by Ca2+ and protein kinase C in endothelin-stimulated Rat-1 cells. Biochem J. 1997 Feb 1;321(Pt 3):795–804. doi: 10.1042/bj3210795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cao L., Wu J., Gardner D. G. Atrial natriuretic peptide suppresses the transcription of its guanylyl cyclase-linked receptor. J Biol Chem. 1995 Oct 20;270(42):24891–24897. doi: 10.1074/jbc.270.42.24891. [DOI] [PubMed] [Google Scholar]
- Colbert M. C., Hall D. G., Kimball T. R., Witt S. A., Lorenz J. N., Kirby M. L., Hewett T. E., Klevitsky R., Robbins J. Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice. J Clin Invest. 1997 Oct 15;100(8):1958–1968. doi: 10.1172/JCI119727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dyson E., Sucov H. M., Kubalak S. W., Schmid-Schönbein G. W., DeLano F. A., Evans R. M., Ross J., Jr, Chien K. R. Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha -/- mice. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7386–7390. doi: 10.1073/pnas.92.16.7386. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Esgleyes-Ribot T., Chandraratna R. A., Lew-Kaya D. A., Sefton J., Duvic M. Response of psoriasis to a new topical retinoid, AGN 190168. J Am Acad Dermatol. 1994 Apr;30(4):581–590. doi: 10.1016/s0190-9622(94)70066-4. [DOI] [PubMed] [Google Scholar]
- Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fujitani Y., Ninomiya H., Okada T., Urade Y., Masaki T. Suppression of endothelin-1-induced mitogenic responses of human aortic smooth muscle cells by interleukin-1 beta. J Clin Invest. 1995 Jun;95(6):2474–2482. doi: 10.1172/JCI117948. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gruber P. J., Kubalak S. W., Pexieder T., Sucov H. M., Evans R. M., Chien K. R. RXR alpha deficiency confers genetic susceptibility for aortic sac, conotruncal, atrioventricular cushion, and ventricular muscle defects in mice. J Clin Invest. 1996 Sep 15;98(6):1332–1343. doi: 10.1172/JCI118920. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heyman R. A., Mangelsdorf D. J., Dyck J. A., Stein R. B., Eichele G., Evans R. M., Thaller C. 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992 Jan 24;68(2):397–406. doi: 10.1016/0092-8674(92)90479-v. [DOI] [PubMed] [Google Scholar]
- Irons C. E., Flynn M. A., Mok L. M., Reynolds E. E. Endothelin and PDGF enhance arachidonic acid release and DNA synthesis in vascular smooth muscle cells. Am J Physiol. 1996 Jun;270(6 Pt 1):C1642–C1646. doi: 10.1152/ajpcell.1996.270.6.C1642. [DOI] [PubMed] [Google Scholar]
- Kastner P., Grondona J. M., Mark M., Gansmuller A., LeMeur M., Decimo D., Vonesch J. L., Dollé P., Chambon P. Genetic analysis of RXR alpha developmental function: convergence of RXR and RAR signaling pathways in heart and eye morphogenesis. Cell. 1994 Sep 23;78(6):987–1003. doi: 10.1016/0092-8674(94)90274-7. [DOI] [PubMed] [Google Scholar]
- Kastner P., Mark M., Chambon P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell. 1995 Dec 15;83(6):859–869. doi: 10.1016/0092-8674(95)90202-3. [DOI] [PubMed] [Google Scholar]
- Kawa S., Nikaido T., Aoki Y., Zhai Y., Kumagaya T., Furihata K., Fujii S., Kiyosawa K. Arotinoid mofarotene (RO40-8757) up-regulates p21 and p27 during growth inhibition of pancreatic cancer cell lines. Int J Cancer. 1997 Sep 4;72(5):906–911. doi: 10.1002/(sici)1097-0215(19970904)72:5<906::aid-ijc31>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
- Lammer E. J., Chen D. T., Hoar R. M., Agnish N. D., Benke P. J., Braun J. T., Curry C. J., Fernhoff P. M., Grix A. W., Jr, Lott I. T. Retinoic acid embryopathy. N Engl J Med. 1985 Oct 3;313(14):837–841. doi: 10.1056/NEJM198510033131401. [DOI] [PubMed] [Google Scholar]
- Langenfeld J., Kiyokawa H., Sekula D., Boyle J., Dmitrovsky E. Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12070–12074. doi: 10.1073/pnas.94.22.12070. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu M., Iavarone A., Freedman L. P. Transcriptional activation of the human p21(WAF1/CIP1) gene by retinoic acid receptor. Correlation with retinoid induction of U937 cell differentiation. J Biol Chem. 1996 Dec 6;271(49):31723–31728. doi: 10.1074/jbc.271.49.31723. [DOI] [PubMed] [Google Scholar]
- Masood I., Porter K. E., London N. J. Endothelin-1 is a mediator of intimal hyperplasia in organ culture of human saphenous vein. Br J Surg. 1997 Apr;84(4):499–503. [PubMed] [Google Scholar]
- Matsushime H., Roussel M. F., Ashmun R. A., Sherr C. J. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell. 1991 May 17;65(4):701–713. doi: 10.1016/0092-8674(91)90101-4. [DOI] [PubMed] [Google Scholar]
- Mendelsohn C., Lohnes D., Décimo D., Lufkin T., LeMeur M., Chambon P., Mark M. Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants. Development. 1994 Oct;120(10):2749–2771. doi: 10.1242/dev.120.10.2749. [DOI] [PubMed] [Google Scholar]
- Miano J. M., Topouzis S., Majesky M. W., Olson E. N. Retinoid receptor expression and all-trans retinoic acid-mediated growth inhibition in vascular smooth muscle cells. Circulation. 1996 May 15;93(10):1886–1895. doi: 10.1161/01.cir.93.10.1886. [DOI] [PubMed] [Google Scholar]
- Mitsuhashi T., Morris R. C., Jr, Ives H. E. 1,25-dihydroxyvitamin D3 modulates growth of vascular smooth muscle cells. J Clin Invest. 1991 Jun;87(6):1889–1895. doi: 10.1172/JCI115213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morey A. K., Pedram A., Razandi M., Prins B. A., Hu R. M., Biesiada E., Levin E. R. Estrogen and progesterone inhibit vascular smooth muscle proliferation. Endocrinology. 1997 Aug;138(8):3330–3339. doi: 10.1210/endo.138.8.5354. [DOI] [PubMed] [Google Scholar]
- Naka K., Yokozaki H., Domen T., Hayashi K., Kuniyasu H., Yasui W., Lotan R., Tahara E. Growth inhibition of cultured human gastric cancer cells by 9-cis-retinoic acid with induction of cdk inhibitor Waf1/Cip1/Sdi1/p21 protein. Differentiation. 1997 Aug;61(5):313–320. doi: 10.1046/j.1432-0436.1997.6150313.x. [DOI] [PubMed] [Google Scholar]
- Owens G. K. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995 Jul;75(3):487–517. doi: 10.1152/physrev.1995.75.3.487. [DOI] [PubMed] [Google Scholar]
- Schieffer B., Drexler H., Ling B. N., Marrero M. B. G protein-coupled receptors control vascular smooth muscle cell proliferation via pp60c-src and p21ras. Am J Physiol. 1997 Jun;272(6 Pt 1):C2019–C2030. doi: 10.1152/ajpcell.1997.272.6.C2019. [DOI] [PubMed] [Google Scholar]
- Sherr C. J. Cancer cell cycles. Science. 1996 Dec 6;274(5293):1672–1677. doi: 10.1126/science.274.5293.1672. [DOI] [PubMed] [Google Scholar]
- Shim J., Lee H., Park J., Kim H., Choi E. J. A non-enzymatic p21 protein inhibitor of stress-activated protein kinases. Nature. 1996 Jun 27;381(6585):804–806. doi: 10.1038/381804a0. [DOI] [PubMed] [Google Scholar]
- Standeven A. M., Escobar M., Beard R. L., Yuan Y. D., Chandraratna R. A. Mitogenic effect of retinoid X receptor agonists in rat liver. Biochem Pharmacol. 1997 Aug 15;54(4):517–524. doi: 10.1016/s0006-2952(97)00209-8. [DOI] [PubMed] [Google Scholar]
- Sucov H. M., Dyson E., Gumeringer C. L., Price J., Chien K. R., Evans R. M. RXR alpha mutant mice establish a genetic basis for vitamin A signaling in heart morphogenesis. Genes Dev. 1994 May 1;8(9):1007–1018. doi: 10.1101/gad.8.9.1007. [DOI] [PubMed] [Google Scholar]
- Teixeira C., Pratt M. A. CDK2 is a target for retinoic acid-mediated growth inhibition in MCF-7 human breast cancer cells. Mol Endocrinol. 1997 Aug;11(9):1191–1202. doi: 10.1210/mend.11.9.9977. [DOI] [PubMed] [Google Scholar]
- Warrell R. P., Jr, de Thé H., Wang Z. Y., Degos L. Acute promyelocytic leukemia. N Engl J Med. 1993 Jul 15;329(3):177–189. doi: 10.1056/NEJM199307153290307. [DOI] [PubMed] [Google Scholar]
- Waskiewicz A. J., Cooper J. A. Mitogen and stress response pathways: MAP kinase cascades and phosphatase regulation in mammals and yeast. Curr Opin Cell Biol. 1995 Dec;7(6):798–805. doi: 10.1016/0955-0674(95)80063-8. [DOI] [PubMed] [Google Scholar]
- Weber H., Webb M. L., Serafino R., Taylor D. S., Moreland S., Norman J., Molloy C. J. Endothelin-1 and angiotensin-II stimulate delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for common signaling mechanisms. Mol Endocrinol. 1994 Feb;8(2):148–158. doi: 10.1210/mend.8.2.8170471. [DOI] [PubMed] [Google Scholar]
- Whelchel A., Evans J., Posada J. Inhibition of ERK activation attenuates endothelin-stimulated airway smooth muscle cell proliferation. Am J Respir Cell Mol Biol. 1997 May;16(5):589–596. doi: 10.1165/ajrcmb.16.5.9160841. [DOI] [PubMed] [Google Scholar]
- Wu J., Garami M., Cheng T., Gardner D. G. 1,25(OH)2 vitamin D3, and retinoic acid antagonize endothelin-stimulated hypertrophy of neonatal rat cardiac myocytes. J Clin Invest. 1996 Apr 1;97(7):1577–1588. doi: 10.1172/JCI118582. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhou M. D., Sucov H. M., Evans R. M., Chien K. R. Retinoid-dependent pathways suppress myocardial cell hypertrophy. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7391–7395. doi: 10.1073/pnas.92.16.7391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhou Q., Stetler-Stevenson M., Steeg P. S. Inhibition of cyclin D expression in human breast carcinoma cells by retinoids in vitro. Oncogene. 1997 Jul 3;15(1):107–115. doi: 10.1038/sj.onc.1201142. [DOI] [PubMed] [Google Scholar]