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. 1989 Mar 1;108(3):1053–1065. doi: 10.1083/jcb.108.3.1053

The actions of retinoids on cellular growth correlate with their actions on gap junctional communication

PMCID: PMC2115395  PMID: 2921279

Abstract

Retinoic acid (a possible morphogen), its biological precursor retinol, and certain synthetic derivatives of retinol profoundly change junctional intercellular communication and growth (saturation density) in 10T 1/2 and 3T3 cells and in their transformed counterparts. The changes correlate: growth decreases as the steady-state junctional permeability rises, and growth increases as that permeability falls. Retinoic acid and retinol exert quite different steady-state actions on communication at noncytotoxic concentrations in the normal cells: retinoic acid inhibits communication at 10(-10)-10(-9) M and enhances at 10(-9)-10(-7) M, whereas retinol only enhances (10(-8)-10(-6) M). In v-mos-transformed cells the enhancement is altogether lacking. But regardless of the retinoid or cell type, all growth responses show essentially the same dependence on junctional permeability. This is the expected behavior if the cell-to-cell channels of gap junctions disseminate growth-regulating signals through cell populations.

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Selected References

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  1. Aaronson S. A., Todaro G. J. Development of 3T3-like lines from Balb-c mouse embryo cultures: transformation susceptibility to SV40. J Cell Physiol. 1968 Oct;72(2):141–148. doi: 10.1002/jcp.1040720208. [DOI] [PubMed] [Google Scholar]
  2. Bertram J. S. Structure-activity relationships among various retinoids and their ability to inhibit neoplastic transformation and to increase cell adhesion in the C3H/10T1/2 CL8 cell line. Cancer Res. 1980 Sep;40(9):3141–3146. [PubMed] [Google Scholar]
  3. Blair D. G., McClements W. L., Oskarsson M. K., Fischinger P. J., Vande Woude G. F. Biological activity of cloned Moloney sarcoma virus DNA: Terminally redundant sequences may enhance transformation efficiency. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3504–3508. doi: 10.1073/pnas.77.6.3504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brand N., Petkovich M., Krust A., Chambon P., de Thé H., Marchio A., Tiollais P., Dejean A. Identification of a second human retinoic acid receptor. Nature. 1988 Apr 28;332(6167):850–853. doi: 10.1038/332850a0. [DOI] [PubMed] [Google Scholar]
  5. Burton A. C. Cellular communication, contact inhibition, cell clocks, and cancer: the impact of the work and ideas of W. R. Loewenstein. Perspect Biol Med. 1971 Winter;14(2):301–318. doi: 10.1353/pbm.1971.0008. [DOI] [PubMed] [Google Scholar]
  6. Croy R. G., Pardee A. B. Enhanced synthesis and stabilization of Mr 68,000 protein in transformed BALB/c-3T3 cells: candidate for restriction point control of cell growth. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4699–4703. doi: 10.1073/pnas.80.15.4699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Elias P. M., Friend D. S. Vitamin-A-induced mucous metaplasia. An in vitro system for modulating tight and gap junction differentiation. J Cell Biol. 1976 Feb;68(2):173–188. doi: 10.1083/jcb.68.2.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Elias P. M., Grayson S., Caldwell T. M., McNutt N. S. Gap junction proliferation in retinoic acid-treated human basal cell carcinoma. Lab Invest. 1980 Apr;42(4):469–474. [PubMed] [Google Scholar]
  9. Fraser S. E., Green C. R., Bode H. R., Gilula N. B. Selective disruption of gap junctional communication interferes with a patterning process in hydra. Science. 1987 Jul 3;237(4810):49–55. doi: 10.1126/science.3037697. [DOI] [PubMed] [Google Scholar]
  10. Fuchs E., Green H. Regulation of terminal differentiation of cultured human keratinocytes by vitamin A. Cell. 1981 Sep;25(3):617–625. doi: 10.1016/0092-8674(81)90169-0. [DOI] [PubMed] [Google Scholar]
  11. Giguere V., Ong E. S., Segui P., Evans R. M. Identification of a receptor for the morphogen retinoic acid. Nature. 1987 Dec 17;330(6149):624–629. doi: 10.1038/330624a0. [DOI] [PubMed] [Google Scholar]
  12. Gubler M. L., Sherman M. I. Metabolism of retinoids by embryonal carcinoma cells. J Biol Chem. 1985 Aug 15;260(17):9552–9558. [PubMed] [Google Scholar]
  13. Haddox M. K., Scott K. F., Russell D. H. Retinol inhibition of ornithine decarboxylase induction and G1 progression in Chinese hamster ovary cells. Cancer Res. 1979 Dec;39(12):4930–4938. [PubMed] [Google Scholar]
  14. Linnenbach A., Huebner K., Croce C. M. DNA-transformed murine teratocarcinoma cells: regulation of expression of simian virus 40 tumor antigen in stem versus differentiated cells. Proc Natl Acad Sci U S A. 1980 Aug;77(8):4875–4879. doi: 10.1073/pnas.77.8.4875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Loewenstein W. R., Azarnia R. Regulation of intercellular communication and growth by the cellular src gene. Ann N Y Acad Sci. 1988;551:337–346. doi: 10.1111/j.1749-6632.1988.tb22359.x. [DOI] [PubMed] [Google Scholar]
  16. Loewenstein W. R. Junctional intercellular communication and the control of growth. Biochim Biophys Acta. 1979 Feb 4;560(1):1–65. doi: 10.1016/0304-419x(79)90002-7. [DOI] [PubMed] [Google Scholar]
  17. Loewenstein W. R. Permeability of membrane junctions. Ann N Y Acad Sci. 1966 Jul 14;137(2):441–472. doi: 10.1111/j.1749-6632.1966.tb50175.x. [DOI] [PubMed] [Google Scholar]
  18. Loewenstein W. R. The cell-to-cell channel of gap junctions. Cell. 1987 Mar 13;48(5):725–726. doi: 10.1016/0092-8674(87)90067-5. [DOI] [PubMed] [Google Scholar]
  19. Loewenstein W. R. Transfer of information through cell junctions and growth control. Proc Can Cancer Conf. 1969;8:162–170. [PubMed] [Google Scholar]
  20. Lotan R. Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochim Biophys Acta. 1980 Mar 12;605(1):33–91. doi: 10.1016/0304-419x(80)90021-9. [DOI] [PubMed] [Google Scholar]
  21. Maden M. Vitamin A and pattern formation in the regenerating limb. Nature. 1982 Feb 25;295(5851):672–675. doi: 10.1038/295672a0. [DOI] [PubMed] [Google Scholar]
  22. Mehta P. P., Bertram J. S., Loewenstein W. R. Growth inhibition of transformed cells correlates with their junctional communication with normal cells. Cell. 1986 Jan 17;44(1):187–196. doi: 10.1016/0092-8674(86)90497-6. [DOI] [PubMed] [Google Scholar]
  23. Mordan L. J., Bertram J. S. Retinoid effects on cell-cell interactions and growth characteristics of normal and carcinogen-treated C3H/1OT1/2 cells. Cancer Res. 1983 Feb;43(2):567–571. [PubMed] [Google Scholar]
  24. Napoli J. L. Retinol metabolism in LLC-PK1 Cells. Characterization of retinoic acid synthesis by an established mammalian cell line. J Biol Chem. 1986 Oct 15;261(29):13592–13597. [PubMed] [Google Scholar]
  25. PUCK T. T., MARCUS P. I., CIECIURA S. J. Clonal growth of mammalian cells in vitro; growth characteristics of colonies from single HeLa cells with and without a feeder layer. J Exp Med. 1956 Feb 1;103(2):273–283. doi: 10.1084/jem.103.2.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Petkovich M., Brand N. J., Krust A., Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987 Dec 3;330(6147):444–450. doi: 10.1038/330444a0. [DOI] [PubMed] [Google Scholar]
  27. Pitts J. D., Hamilton A. E., Kam E., Burk R. R., Murphy J. P. Retinoic acid inhibits junctional communication between animal cells. Carcinogenesis. 1986 Jun;7(6):1003–1010. doi: 10.1093/carcin/7.6.1003. [DOI] [PubMed] [Google Scholar]
  28. Prutkin L. Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, keratoacanthoma. Cancer Res. 1975 Feb;35(2):364–369. [PubMed] [Google Scholar]
  29. Reznikoff C. A., Bertram J. S., Brankow D. W., Heidelberger C. Quantitative and qualitative studies of chemical transformation of cloned C3H mouse embryo cells sensitive to postconfluence inhibition of cell division. Cancer Res. 1973 Dec;33(12):3239–3249. [PubMed] [Google Scholar]
  30. Rundhaug J., Gubler M. L., Sherman M. I., Blaner W. S., Bertram J. S. Differential uptake, binding, and metabolism of retinol and retinoic acid by 10T1/2 cells. Cancer Res. 1987 Nov 1;47(21):5637–5643. [PubMed] [Google Scholar]
  31. Schroder E. W., Black P. H. Retinoids: tumor preventers or tumor enhancers? J Natl Cancer Inst. 1980 Oct;65(4):671–674. doi: 10.1093/jnci/65.4.671. [DOI] [PubMed] [Google Scholar]
  32. Simpson I., Rose B., Loewenstein W. R. Size limit of molecules permeating the junctional membrane channels. Science. 1977 Jan 21;195(4275):294–296. doi: 10.1126/science.831276. [DOI] [PubMed] [Google Scholar]
  33. Strickland S., Mahdavi V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell. 1978 Oct;15(2):393–403. doi: 10.1016/0092-8674(78)90008-9. [DOI] [PubMed] [Google Scholar]
  34. Thaller C., Eichele G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature. 1987 Jun 18;327(6123):625–628. doi: 10.1038/327625a0. [DOI] [PubMed] [Google Scholar]
  35. Tickle C., Alberts B., Wolpert L., Lee J. Local application of retinoic acid to the limb bond mimics the action of the polarizing region. Nature. 1982 Apr 8;296(5857):564–566. doi: 10.1038/296564a0. [DOI] [PubMed] [Google Scholar]
  36. Warner A. E., Guthrie S. C., Gilula N. B. Antibodies to gap-junctional protein selectively disrupt junctional communication in the early amphibian embryo. Nature. 1984 Sep 13;311(5982):127–131. doi: 10.1038/311127a0. [DOI] [PubMed] [Google Scholar]
  37. Wolf G. Multiple functions of vitamin A. Physiol Rev. 1984 Jul;64(3):873–937. doi: 10.1152/physrev.1984.64.3.873. [DOI] [PubMed] [Google Scholar]
  38. Wälder L., Lützelschwab R. Effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), retinoic acid and diazepam on intercellular communication in a monolayer of rat liver epithelial cells. Exp Cell Res. 1984 May;152(1):66–76. doi: 10.1016/0014-4827(84)90230-1. [DOI] [PubMed] [Google Scholar]
  39. Yada T., Rose B., Loewenstein W. R. Diacylglycerol downregulates junctional membrane permeability. TMB-8 blocks this effect. J Membr Biol. 1985;88(3):217–232. doi: 10.1007/BF01871087. [DOI] [PubMed] [Google Scholar]
  40. Yamamoto K. R., Alberts B. M. Steroid receptors: elements for modulation of eukaryotic transcription. Annu Rev Biochem. 1976;45:721–746. doi: 10.1146/annurev.bi.45.070176.003445. [DOI] [PubMed] [Google Scholar]

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