Vitamin-Regulated Retinoblastoma Tumor Suppressor Gene Expression in Leukemic Cells

  • Andrew Yen
  • Tracy French
  • Karen Russell
  • Susi Varvayanis
  • Mary Forbes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 375)


Vitamins A and D are well known to perform important functions in growth and development. The mechanisms by which they act at the cellular level to control proliferation and differentiation thus become of importance in understanding how these dietary factors work. Using tissue culture, it has been found that a variety of cultured cells respond in particular to the metabolites, retinoic acid, and 1,25-dihydroxy vitamin D3. These cells have formed convenient experimental systems in which to study the mechanism of action of these metabolites at the molecular level. At this level, it is known that vitamins A and D have receptors that are related as members of the family of steroid-thyroid hormone receptors.1,2 Ligand receptor binding and receptor complex translocation to the nucleus thus regulate gene expression. The ultimate result of a lengthy metabolic cascade initiated this way can be control of cell proliferation or differentiation. The identity and roles of the genes that mediate this metabolic cascade are of obvious interest in understanding the mechanism by which these vitamins or their metabolites act in growth and development.


Retinoic Acid Specific Growth Arrest Metabolic Cascade Retinoblastoma Gene Product Nuclear Oncogene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    R.M. Evans, The steroid and thyroid hormone receptor superfamily, Science 240:889–895 (1988).PubMedCrossRefGoogle Scholar
  2. 2.
    R. Schule, K. Umesono, DJ. Mangelsdorf, J. Bolado, J.W. Pike, R.M. Evans, Jun-fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene, Cell 61:497–504 (1990).PubMedCrossRefGoogle Scholar
  3. 3.
    S.J. Collins, R.C. Gallo, R.E. Gallagher, Continuous growth and differentiation of human myloid leukemia cells in suspension culture, Nature 270:347–349 (1977).PubMedCrossRefGoogle Scholar
  4. 4.
    A. Yen, HL-60 cells as a model of growth control and differentiation: The significance of variant cells, Hemat Rev 4:5–46 (1990).Google Scholar
  5. 5.
    A. Yen, S.L. Reece, K.L. Albright, Dependence of HL-60 myeloid cell differentiation on continuous and split retinoic acid exposures: Pre-commitment memory associated with altered nuclear structure, J Cell Physiol 118:277–286 (1984).PubMedCrossRefGoogle Scholar
  6. 6.
    A. Yen, M.E. Forbes, c-myc Down regulation and precommitment in HL-60 cells due to bromodeoxyuridine, Cancer Res 50:1411–1420 (1990).PubMedGoogle Scholar
  7. 7.
    A. Yen, M. Forbes, G. deGala, J. Fishbaugh, Control of HL-60 cell differentiation lineage specificity: A late event occurring after precommitment, Cancer Res 47:129–134 (1987).PubMedGoogle Scholar
  8. 8.
    R. Chiu, W.J. Boyle, J. Meek, T. Smeal, T. Hunter, M. Karin, The c-fos protein interacts with c-jun/AP-1 to stimulate transcription of AP-1 responsive genes, Cell 54:541–552 (1988).PubMedCrossRefGoogle Scholar
  9. 9.
    T. Curran, B.R. Franza, Jr., fos and jun: The AP-1 connection, Cell 55:395–397 (1988).PubMedCrossRefGoogle Scholar
  10. 10.
    R. Turner, R. Tjian, Leucine repeats and an adjacent DNA binding domain mediate the formation of functional cfos-cjun heterodimers, Science 243:1689–1694 (1989).PubMedCrossRefGoogle Scholar
  11. 11.
    R Gentz, F.J. Rauscher, III, C. Abate, T. Curran, Parallel association of fos and jun leucine zippers juxtaposes DNA binding domains, Science 243:1695–1699 (1989).PubMedCrossRefGoogle Scholar
  12. 12.
    T.-K.T. Fung, A.L. Murphree, A. T’Ang, J. Qian, S.H. Hinrichs, W.F. Benedict, Structural evidence for the authenticity of the human retinoblastoma gene, Science 236:1657–1661 (1987).PubMedCrossRefGoogle Scholar
  13. 13.
    W.-H. Lee, R. Bookstein, F. Hong, L.-J. Young, J.-Y. Shew, E.Y.-H.P. Lee, Human retinoblastoma susceptibility gene: Cloning, identification, and sequence, Science 235:1394–1399 (1987).PubMedCrossRefGoogle Scholar
  14. 14.
    S.H. Friend, R. Bernards, S. Rogelj, R.A. Weinberg, J.M. Rapaport, D.M. Albert, T.P. Dryja, A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma, Nature 323:643–646 (1986).PubMedCrossRefGoogle Scholar
  15. 15.
    K. Mihara, X.-R. Cao, A. Yen, S. Chandler, B. Driscoll, A.L. Murphree, A. T’Ang, Y.K.T. Fung, Cell-cycle dependent regulation of phosphorylation of the human retinoblastoma gene product, Science 246:1300–1303 (1989).PubMedCrossRefGoogle Scholar
  16. 16.
    P.-L. Chen, P. Scully, J.-Y. Shew, J.YJ. Wang, W.-H. Lee, Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation, Cell 58:1193–1198 (1989).PubMedCrossRefGoogle Scholar
  17. 17.
    P.D. Robbins, J.M. Horowitz, R.C. Mulligan, Negative regulation of human c-fos expression by the retinoblastoma gene product, Nature 346:668–671 (1990).PubMedCrossRefGoogle Scholar
  18. P.D. Robbins, J.M. Horowitz, R.C. Mulligan, Negative regulation of human c-fos expression by the retinoblastoma gene product ibid. Nature 351:419 (1991).Google Scholar
  19. 18.
    M.M. Ouellette, J. Chen, WE. Wright, J.W Shay, Complexes containing the retinoblastoma gene product recognize different DNA motifs related to the E2F binding site, Oncogene 7:1075–1081 (1992).PubMedGoogle Scholar
  20. 19.
    P.A. Hamel, R.M. Gill, R.A. Phillips, B.L. Gallie, Transcriptional repression of the E2-containing promoters EIIaE, c-myc, and RBI by the product of the RBI gene, Molec Cell Biol 12:3431–3438 (1992).PubMedGoogle Scholar
  21. 20.
    S.J. Weintraub, C.A. Prater, D.C. Dean, Retinoblastoma protein switches the E2F site from positive to negative element, Nature 358:259–261 (1992).PubMedCrossRefGoogle Scholar
  22. 21.
    A. Yen, S. Chandler, S. Sturzenegger-Varvayanis, Regulated expression of the RB “tumor suppressor gene” in normal lymphocyte mitogenesis: Elevated expression in transformed leukocytes and role as a “status quo” gene, Experimental Cell Research 192:289–297 (1991).PubMedCrossRefGoogle Scholar
  23. 22.
    W. Zhang, W. Hittelman, N. Van, M. Andreeff, A. Deisseroth, The phosphorylation of retinoblastoma gene product in human myeloid leukemia cells during the cell cycle, Biochem Biophys Res Comm 184:212–216 (1992).PubMedCrossRefGoogle Scholar
  24. 23.
    A. Yen, S. Chandler, Inducers of leukemic cell differentiation cause down-regulation of RB gene expression, Proc Soc Exper Bio Med 199:291–297 (1992).CrossRefGoogle Scholar
  25. 24.
    A. Yen, S. Chandler, M.E. Forbes, Y.-K. Fung, A. T’Ang, R. Pearson, Coupled down-regulation of the RB retinoblastoma and c-myc genes antecedes cell differentiation: Possible role of RB as a “status quo” gene, Eur J Cell Biol 57:210–221 (1992).PubMedGoogle Scholar
  26. 25.
    J.W. Ludlow, J.A. DeCaprio, C.-M. Huang, W.-H. Lee, E. Paucha, D.M. Livingston, SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family, Cell 56:57–65 (1989).PubMedCrossRefGoogle Scholar
  27. 26.
    J.W. Ludlow, J. Shon, J.M. Pipas, D.M. Livingston, J.A. DeCaprio, The retinoblastoma susceptibility gene product undergoes cell cycle-dependent dephosphorylation and binding to and release from SV40 large T, Cell 60:387–396 (1990).PubMedCrossRefGoogle Scholar
  28. 27.
    L. Szekely, E. Uzvolgyi, W.-Q. Jiang, M. Durko, K.G. Wiman, G. Klein, J. Sumegi, Subcellular localization of the retinoblastoma protein, Cell Growth and Differentiation 2:287–295 (1991).PubMedGoogle Scholar
  29. 28.
    B. Alberts, D. Bray, J. Lewis, M. Raff, K. Roberts, J.D. Watson, Renewal by pluripotent stem cells: Blood cell formation, in: Molecular Biology of the Cell, 2nd Ed. p.973, Garland Publishing, New York (1989).Google Scholar
  30. 29.
    P.J. Quesenberry, Hemopoietic stem cells, progenitor cells, and growth factors, in: Hematology, 4th Ed. W. J. Williams, E. Beutler, A.J. Erslev, M.A. Lichtmen, eds. p. 129, McGraw-Hill, New York (1990).Google Scholar
  31. 30.
    H.E. Broxmeyer, D.E. Williams, G. Hangoc, S. Cooper, S. Gillis, R.K. Shadduck, D.C. Bicknell, Synergistic myelopoietic actions in vivo after administration to mice of combinations of purified natural murine colony-stimulating factor 1, recombinant murine interleukin 3, and recombinant murine granulocyte/macrophage colony-stimulating factor, Proc Natl Acad Sci 84:3871–3875 (1987).PubMedCrossRefGoogle Scholar
  32. 31.
    R. Muller, D.J. Slamon, E.D. Adamson, J.M. Tremblay, D. Muller, M.J. Cline, I.M. Verma, Transcription of c-onc genes c-ras ki and c-fins during mouse development, Molec Cell Biol 3:1062–1069 (1983).PubMedGoogle Scholar
  33. 32.
    P.T. Rowley, B. Farley, R. Giuliano, S. LaBella, J.F. Leary, Induction of the FMS protooncogene product in HL-60 cells by vitamin D: A flow cytometric analysis, Leuk Res 16:403–410 (1992).PubMedCrossRefGoogle Scholar
  34. 33.
    C.J. Sherr, R.A. Ahmun, J.R. Downing, M. Ohtsuka, S.G. Quan, D.W. Golde, M.F. Roussel, Inhibition of colony stimulating factor-1 activity by monoclonal antibodies to the human CSF-1 receptor, Blood 73:1786–1793 (1989).PubMedGoogle Scholar
  35. 34.
    S. Mittnacht, R.A. Weinberg, Gl/S phosphorylation of the retinoblastoma protein is associated with an altered affinity for the nuclear compartment, Cell 65:381–393 (1991).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Andrew Yen
    • 1
  • Tracy French
    • 1
  • Karen Russell
    • 1
  • Susi Varvayanis
    • 1
  • Mary Forbes
    • 1
  1. 1.Cancer Biology Laboratories, Department of Pathology, College of Veterinary MedicineCornell UniversityIthacaUSA

Personalised recommendations