Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jul 18;92(15):6837–6841. doi: 10.1073/pnas.92.15.6837

Rescue of defective mitogenic signaling by D-type cyclins.

M F Roussel 1, A M Theodoras 1, M Pagano 1, C J Sherr 1
PMCID: PMC41424  PMID: 7624328

Abstract

Three gene products, including Myc and the D- and E-type G1 cyclins, are rate limiting for G1 progression in mammalian fibroblasts. Quiescent mouse NIH 3T3 fibroblasts engineered to express a mutant colony-stimulating factor (CSF-1) receptor (CSF-1R 809F) fail to synthesize c-myc and cyclin D1 mRNAs upon CSF-1 stimulation and remain arrested in early G1 phase. Ectopic expression of c-myc or either of three D-type cyclin genes, but not cyclin E, resensitized these cells to the mitogenic effects of CSF-1, enabling them to proliferate continuously in liquid culture and to form colonies in agar in response to the growth factor. Rescue by cyclin D1 was enhanced by c-myc but not by cyclin E and was reversed by infecting cyclin D1-reconstituted cells with a retroviral vector encoding catalytically inactive cyclin-dependent kinase 4. Induction of cyclin D1 mRNA by CSF-1 was restored in cells forced to express c-myc, and vice versa, suggesting that expression of the two genes is interdependent. Cells reconstituted with c-myc were prevented from entering S phase when microinjected with a monoclonal antibody to cyclin D1, and conversely, those rescued by cyclin D1 were inhibited from forming CSF-1-dependent colonies when challenged with a dominant-negative c-myc mutant. Cyclin D mutants defective in binding to the retinoblastoma protein were impaired in rescuing mitogenic signaling. Therefore, Myc and D-type cyclins collaborate during the mitogenic response to CSF-1, whereas cyclin E functions in a separate pathway.

Full text

PDF
6839

Images in this article

6838Fig. 1
on p.6838
6839Fig. 2
on p.6839
6840Fig. 3
on p.6840

Selected References

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

  1. Anderson S. J., Gonda M. A., Rettenmier C. W., Sherr C. J. Subcellular localization of glycoproteins encoded by the viral oncogene v-fms. J Virol. 1984 Sep;51(3):730–741. doi: 10.1128/jvi.51.3.730-741.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ansorge W., Pepperkok R. Performance of an automated system for capillary microinjection into living cells. J Biochem Biophys Methods. 1988 Aug;16(4):283–292. doi: 10.1016/0165-022x(88)90062-0. [DOI] [PubMed] [Google Scholar]
  3. Baldin V., Lukas J., Marcote M. J., Pagano M., Draetta G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 1993 May;7(5):812–821. doi: 10.1101/gad.7.5.812. [DOI] [PubMed] [Google Scholar]
  4. Bates S., Bonetta L., MacAllan D., Parry D., Holder A., Dickson C., Peters G. CDK6 (PLSTIRE) and CDK4 (PSK-J3) are a distinct subset of the cyclin-dependent kinases that associate with cyclin D1. Oncogene. 1994 Jan;9(1):71–79. [PubMed] [Google Scholar]
  5. Bodrug S. E., Warner B. J., Bath M. L., Lindeman G. J., Harris A. W., Adams J. M. Cyclin D1 transgene impedes lymphocyte maturation and collaborates in lymphomagenesis with the myc gene. EMBO J. 1994 May 1;13(9):2124–2130. doi: 10.1002/j.1460-2075.1994.tb06488.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chen P. L., Scully P., Shew J. Y., Wang J. Y., Lee W. H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell. 1989 Sep 22;58(6):1193–1198. doi: 10.1016/0092-8674(89)90517-5. [DOI] [PubMed] [Google Scholar]
  7. Cleveland J. L., Dean M., Rosenberg N., Wang J. Y., Rapp U. R. Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl. Mol Cell Biol. 1989 Dec;9(12):5685–5695. doi: 10.1128/mcb.9.12.5685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Daksis J. I., Lu R. Y., Facchini L. M., Marhin W. W., Penn L. J. Myc induces cyclin D1 expression in the absence of de novo protein synthesis and links mitogen-stimulated signal transduction to the cell cycle. Oncogene. 1994 Dec;9(12):3635–3645. [PubMed] [Google Scholar]
  9. Dowdy S. F., Hinds P. W., Louie K., Reed S. I., Arnold A., Weinberg R. A. Physical interaction of the retinoblastoma protein with human D cyclins. Cell. 1993 May 7;73(3):499–511. doi: 10.1016/0092-8674(93)90137-f. [DOI] [PubMed] [Google Scholar]
  10. Downing J. R., Rettenmier C. W., Sherr C. J. Ligand-induced tyrosine kinase activity of the colony-stimulating factor 1 receptor in a murine macrophage cell line. Mol Cell Biol. 1988 Apr;8(4):1795–1799. doi: 10.1128/mcb.8.4.1795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dulić V., Lees E., Reed S. I. Association of human cyclin E with a periodic G1-S phase protein kinase. Science. 1992 Sep 25;257(5078):1958–1961. doi: 10.1126/science.1329201. [DOI] [PubMed] [Google Scholar]
  12. Ewen M. E., Sluss H. K., Sherr C. J., Matsushime H., Kato J., Livingston D. M. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell. 1993 May 7;73(3):487–497. doi: 10.1016/0092-8674(93)90136-e. [DOI] [PubMed] [Google Scholar]
  13. Hinds P. W., Dowdy S. F., Eaton E. N., Arnold A., Weinberg R. A. Function of a human cyclin gene as an oncogene. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):709–713. doi: 10.1073/pnas.91.2.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jansen-Dürr P., Meichle A., Steiner P., Pagano M., Finke K., Botz J., Wessbecher J., Draetta G., Eilers M. Differential modulation of cyclin gene expression by MYC. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3685–3689. doi: 10.1073/pnas.90.8.3685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Karn J., Watson J. V., Lowe A. D., Green S. M., Vedeckis W. Regulation of cell cycle duration by c-myc levels. Oncogene. 1989 Jun;4(6):773–787. [PubMed] [Google Scholar]
  16. Kato J., Matsushime H., Hiebert S. W., Ewen M. E., Sherr C. J. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 1993 Mar;7(3):331–342. doi: 10.1101/gad.7.3.331. [DOI] [PubMed] [Google Scholar]
  17. Koff A., Giordano A., Desai D., Yamashita K., Harper J. W., Elledge S., Nishimoto T., Morgan D. O., Franza B. R., Roberts J. M. Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. Science. 1992 Sep 18;257(5077):1689–1694. doi: 10.1126/science.1388288. [DOI] [PubMed] [Google Scholar]
  18. Lovec H., Grzeschiczek A., Kowalski M. B., Möröy T. Cyclin D1/bcl-1 cooperates with myc genes in the generation of B-cell lymphoma in transgenic mice. EMBO J. 1994 Aug 1;13(15):3487–3495. doi: 10.1002/j.1460-2075.1994.tb06655.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lovec H., Sewing A., Lucibello F. C., Müller R., Möröy T. Oncogenic activity of cyclin D1 revealed through cooperation with Ha-ras: link between cell cycle control and malignant transformation. Oncogene. 1994 Jan;9(1):323–326. [PubMed] [Google Scholar]
  20. Ludlow J. W., Shon J., Pipas J. M., Livingston D. M., DeCaprio J. A. The retinoblastoma susceptibility gene product undergoes cell cycle-dependent dephosphorylation and binding to and release from SV40 large T. Cell. 1990 Feb 9;60(3):387–396. doi: 10.1016/0092-8674(90)90590-b. [DOI] [PubMed] [Google Scholar]
  21. Lukas J., Bartkova J., Rohde M., Strauss M., Bartek J. Cyclin D1 is dispensable for G1 control in retinoblastoma gene-deficient cells independently of cdk4 activity. Mol Cell Biol. 1995 May;15(5):2600–2611. doi: 10.1128/mcb.15.5.2600. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lukas J., Pagano M., Staskova Z., Draetta G., Bartek J. Cyclin D1 protein oscillates and is essential for cell cycle progression in human tumour cell lines. Oncogene. 1994 Mar;9(3):707–718. [PubMed] [Google Scholar]
  23. Matsushime H., Ewen M. E., Strom D. K., Kato J. Y., Hanks S. K., Roussel M. F., Sherr C. J. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell. 1992 Oct 16;71(2):323–334. doi: 10.1016/0092-8674(92)90360-o. [DOI] [PubMed] [Google Scholar]
  24. Matsushime H., Quelle D. E., Shurtleff S. A., Shibuya M., Sherr C. J., Kato J. Y. D-type cyclin-dependent kinase activity in mammalian cells. Mol Cell Biol. 1994 Mar;14(3):2066–2076. doi: 10.1128/mcb.14.3.2066. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Meyerson M., Harlow E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol. 1994 Mar;14(3):2077–2086. doi: 10.1128/mcb.14.3.2077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ohtsubo M., Roberts J. M. Cyclin-dependent regulation of G1 in mammalian fibroblasts. Science. 1993 Mar 26;259(5103):1908–1912. doi: 10.1126/science.8384376. [DOI] [PubMed] [Google Scholar]
  28. Ohtsubo M., Theodoras A. M., Schumacher J., Roberts J. M., Pagano M. Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. Mol Cell Biol. 1995 May;15(5):2612–2624. doi: 10.1128/mcb.15.5.2612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Oswald F., Lovec H., Möröy T., Lipp M. E2F-dependent regulation of human MYC: trans-activation by cyclins D1 and A overrides tumour suppressor protein functions. Oncogene. 1994 Jul;9(7):2029–2036. [PubMed] [Google Scholar]
  30. Pagano M., Pepperkok R., Lukas J., Baldin V., Ansorge W., Bartek J., Draetta G. Regulation of the cell cycle by the cdk2 protein kinase in cultured human fibroblasts. J Cell Biol. 1993 Apr;121(1):101–111. doi: 10.1083/jcb.121.1.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Philipp A., Schneider A., Väsrik I., Finke K., Xiong Y., Beach D., Alitalo K., Eilers M. Repression of cyclin D1: a novel function of MYC. Mol Cell Biol. 1994 Jun;14(6):4032–4043. doi: 10.1128/mcb.14.6.4032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Quelle D. E., Ashmun R. A., Shurtleff S. A., Kato J. Y., Bar-Sagi D., Roussel M. F., Sherr C. J. Overexpression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes Dev. 1993 Aug;7(8):1559–1571. doi: 10.1101/gad.7.8.1559. [DOI] [PubMed] [Google Scholar]
  33. Resnitzky D., Gossen M., Bujard H., Reed S. I. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system. Mol Cell Biol. 1994 Mar;14(3):1669–1679. doi: 10.1128/mcb.14.3.1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rosenwald I. B., Lazaris-Karatzas A., Sonenberg N., Schmidt E. V. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol Cell Biol. 1993 Dec;13(12):7358–7363. doi: 10.1128/mcb.13.12.7358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Roussel M. F., Cleveland J. L., Shurtleff S. A., Sherr C. J. Myc rescue of a mutant CSF-1 receptor impaired in mitogenic signalling. Nature. 1991 Sep 26;353(6342):361–363. doi: 10.1038/353361a0. [DOI] [PubMed] [Google Scholar]
  36. Roussel M. F., Davis J. N., Cleveland J. L., Ghysdael J., Hiebert S. W. Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1. Oncogene. 1994 Feb;9(2):405–415. [PubMed] [Google Scholar]
  37. Roussel M. F., Dull T. J., Rettenmier C. W., Ralph P., Ullrich A., Sherr C. J. Transforming potential of the c-fms proto-oncogene (CSF-1 receptor). Nature. 1987 Feb 5;325(6104):549–552. doi: 10.1038/325549a0. [DOI] [PubMed] [Google Scholar]
  38. Roussel M. F., Sherr C. J. Mouse NIH 3T3 cells expressing human colony-stimulating factor 1 (CSF-1) receptors overgrow in serum-free medium containing human CSF-1 as their only growth factor. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7924–7927. doi: 10.1073/pnas.86.20.7924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Roussel M. F., Shurtleff S. A., Downing J. R., Sherr C. J. A point mutation at tyrosine-809 in the human colony-stimulating factor 1 receptor impairs mitogenesis without abrogating tyrosine kinase activity, association with phosphatidylinositol 3-kinase, or induction of c-fos and junB genes. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6738–6742. doi: 10.1073/pnas.87.17.6738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sawyers C. L., Callahan W., Witte O. N. Dominant negative MYC blocks transformation by ABL oncogenes. Cell. 1992 Sep 18;70(6):901–910. doi: 10.1016/0092-8674(92)90241-4. [DOI] [PubMed] [Google Scholar]
  41. Shibuya H., Yoneyama M., Ninomiya-Tsuji J., Matsumoto K., Taniguchi T. IL-2 and EGF receptors stimulate the hematopoietic cell cycle via different signaling pathways: demonstration of a novel role for c-myc. Cell. 1992 Jul 10;70(1):57–67. doi: 10.1016/0092-8674(92)90533-i. [DOI] [PubMed] [Google Scholar]
  42. Stone J., de Lange T., Ramsay G., Jakobovits E., Bishop J. M., Varmus H., Lee W. Definition of regions in human c-myc that are involved in transformation and nuclear localization. Mol Cell Biol. 1987 May;7(5):1697–1709. doi: 10.1128/mcb.7.5.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tam S. W., Theodoras A. M., Shay J. W., Draetta G. F., Pagano M. Differential expression and regulation of Cyclin D1 protein in normal and tumor human cells: association with Cdk4 is required for Cyclin D1 function in G1 progression. Oncogene. 1994 Sep;9(9):2663–2674. [PubMed] [Google Scholar]
  44. Tsai L. H., Lees E., Faha B., Harlow E., Riabowol K. The cdk2 kinase is required for the G1-to-S transition in mammalian cells. Oncogene. 1993 Jun;8(6):1593–1602. [PubMed] [Google Scholar]
  45. Vallance S. J., Lee H. M., Roussel M. F., Shurtleff S. A., Kato J. Y., Strom D. K., Sherr C. J. Monoclonal antibodies to mammalian D-type G1 cyclins. Hybridoma. 1994 Feb;13(1):37–44. doi: 10.1089/hyb.1994.13.37. [DOI] [PubMed] [Google Scholar]
  46. Xiong Y., Zhang H., Beach D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell. 1992 Oct 30;71(3):505–514. doi: 10.1016/0092-8674(92)90518-h. [DOI] [PubMed] [Google Scholar]
  47. van den Heuvel S., Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993 Dec 24;262(5142):2050–2054. doi: 10.1126/science.8266103. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES