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. 1996 Nov;70(11):7804–7810. doi: 10.1128/jvi.70.11.7804-7810.1996

Repression of cyclin D1 expression does not contribute to initiation or maintenance of cell transformation by adenovirus type 5 E1.

O Kranenburg 1, P Keblusek 1, A J Van der Eb 1, A Zantema 1
PMCID: PMC190850  PMID: 8892901

Abstract

Expression of the gene encoding the cell cycle regulator cyclin D1 is strongly repressed in adenovirus type 5 E1 (Ad5E1)-transformed cells. Since cyclin D1 is a regulator of cell proliferation, modulation of its abundance may affect cell cycle control. Therefore, we studied the importance of cyclin D1 repression for cell transformation by Ad5E1. We found that forced expression of cyclin D1 does not affect the transforming potential of Ad5E1. Similarly, cyclin D1 overexpression did not affect the efficiency of colony formation, the proliferation rate, or the cell cycle distribution of Ad5E1-transformed cell lines, whereas the colony formation of untransformed cell lines was strongly inhibited. Thus, repression of cyclin D1 expression is not required for initiation or maintenance of cell transformation by Ad5E1. In addition, we show that the growth-suppressive effect of cyclin D1 correlates with cyclin D1 binding to cdk4 rather than to proliferating cell nuclear antigen PCNA.

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Selected References

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  1. Atadja P., Wong H., Veillete C., Riabowol K. Overexpression of cyclin D1 blocks proliferation of normal diploid fibroblasts. Exp Cell Res. 1995 Apr;217(2):205–216. doi: 10.1006/excr.1995.1080. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. 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]
  4. Bates S., Parry D., Bonetta L., Vousden K., Dickson C., Peters G. Absence of cyclin D/cdk complexes in cells lacking functional retinoblastoma protein. Oncogene. 1994 Jun;9(6):1633–1640. [PubMed] [Google Scholar]
  5. Bernards R., Houweling A., Schrier P. I., Bos J. L., Van der Eb A. J. Characterization of cells transformed by Ad5/Ad12 hybrid early region I plasmids. Virology. 1982 Jul 30;120(2):422–432. doi: 10.1016/0042-6822(82)90042-3. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Buchou T., Kranenburg O., van Dam H., Roelen D., Zantema A., Hall F. L., van der Eb A. Increased cyclin A and decreased cyclin D levels in adenovirus 5 E1A-transformed rodent cell lines. Oncogene. 1993 Jul;8(7):1765–1773. [PubMed] [Google Scholar]
  8. DeCaprio J. A., Furukawa Y., Ajchenbaum F., Griffin J. D., Livingston D. M. The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1795–1798. doi: 10.1073/pnas.89.5.1795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dorsman J. C., Hagmeyer B. M., Veenstra J., Elfferich P., Nabben N., Zantema A., van der Eb A. J. The N-terminal region of the adenovirus type 5 E1A proteins can repress expression of cellular genes via two distinct but overlapping domains. J Virol. 1995 May;69(5):2962–2967. doi: 10.1128/jvi.69.5.2962-2967.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Fotedar R., Flatt J., Gupta S., Margolis R. L., Fitzgerald P., Messier H., Fotedar A. Activation-induced T-cell death is cell cycle dependent and regulated by cyclin B. Mol Cell Biol. 1995 Feb;15(2):932–942. doi: 10.1128/mcb.15.2.932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freeman R. S., Estus S., Johnson E. M., Jr Analysis of cell cycle-related gene expression in postmitotic neurons: selective induction of Cyclin D1 during programmed cell death. Neuron. 1994 Feb;12(2):343–355. doi: 10.1016/0896-6273(94)90276-3. [DOI] [PubMed] [Google Scholar]
  14. Goodrich D. W., Wang N. P., Qian Y. W., Lee E. Y., Lee W. H. The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell. 1991 Oct 18;67(2):293–302. doi: 10.1016/0092-8674(91)90181-w. [DOI] [PubMed] [Google Scholar]
  15. Han E. K., Sgambato A., Jiang W., Zhang Y. J., Santella R. M., Doki Y., Cacace A. M., Schieren I., Weinstein I. B. Stable overexpression of cyclin D1 in a human mammary epithelial cell line prolongs the S-phase and inhibits growth. Oncogene. 1995 Mar 2;10(5):953–961. [PubMed] [Google Scholar]
  16. 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]
  17. Hinds P. W., Mittnacht S., Dulic V., Arnold A., Reed S. I., Weinberg R. A. Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. Cell. 1992 Sep 18;70(6):993–1006. doi: 10.1016/0092-8674(92)90249-c. [DOI] [PubMed] [Google Scholar]
  18. Hoang A. T., Cohen K. J., Barrett J. F., Bergstrom D. A., Dang C. V. Participation of cyclin A in Myc-induced apoptosis. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6875–6879. doi: 10.1073/pnas.91.15.6875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Jiang W., Kahn S. M., Zhou P., Zhang Y. J., Cacace A. M., Infante A. S., Doi S., Santella R. M., Weinstein I. B. Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene. 1993 Dec;8(12):3447–3457. [PubMed] [Google Scholar]
  20. 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]
  21. Kranenburg O., van der Eb A. J., Zantema A. Cyclin D1 is an essential mediator of apoptotic neuronal cell death. EMBO J. 1996 Jan 2;15(1):46–54. [PMC free article] [PubMed] [Google Scholar]
  22. Lahti J. M., Xiang J., Heath L. S., Campana D., Kidd V. J. PITSLRE protein kinase activity is associated with apoptosis. Mol Cell Biol. 1995 Jan;15(1):1–11. doi: 10.1128/mcb.15.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lew D. J., Dulić V., Reed S. I. Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast. Cell. 1991 Sep 20;66(6):1197–1206. doi: 10.1016/0092-8674(91)90042-w. [DOI] [PubMed] [Google Scholar]
  24. Li Y., Nichols M. A., Shay J. W., Xiong Y. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res. 1994 Dec 1;54(23):6078–6082. [PubMed] [Google Scholar]
  25. 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]
  26. 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]
  27. 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]
  28. Lukas J., Müller H., Bartkova J., Spitkovsky D., Kjerulff A. A., Jansen-Dürr P., Strauss M., Bartek J. DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1. J Cell Biol. 1994 May;125(3):625–638. doi: 10.1083/jcb.125.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. 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]
  32. Motokura T., Arnold A. Cyclins and oncogenesis. Biochim Biophys Acta. 1993 May 25;1155(1):63–78. doi: 10.1016/0304-419x(93)90022-5. [DOI] [PubMed] [Google Scholar]
  33. Motokura T., Bloom T., Kim H. G., Jüppner H., Ruderman J. V., Kronenberg H. M., Arnold A. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature. 1991 Apr 11;350(6318):512–515. doi: 10.1038/350512a0. [DOI] [PubMed] [Google Scholar]
  34. Musgrove E. A., Lee C. S., Buckley M. F., Sutherland R. L. Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8022–8026. doi: 10.1073/pnas.91.17.8022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Müller H., Lukas J., Schneider A., Warthoe P., Bartek J., Eilers M., Strauss M. Cyclin D1 expression is regulated by the retinoblastoma protein. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):2945–2949. doi: 10.1073/pnas.91.8.2945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pagano M., Theodoras A. M., Tam S. W., Draetta G. F. Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Dev. 1994 Jul 15;8(14):1627–1639. doi: 10.1101/gad.8.14.1627. [DOI] [PubMed] [Google Scholar]
  37. Parry D., Bates S., Mann D. J., Peters G. Lack of cyclin D-Cdk complexes in Rb-negative cells correlates with high levels of p16INK4/MTS1 tumour suppressor gene product. EMBO J. 1995 Feb 1;14(3):503–511. doi: 10.1002/j.1460-2075.1995.tb07026.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. 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]
  40. Serrano M., Hannon G. J., Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993 Dec 16;366(6456):704–707. doi: 10.1038/366704a0. [DOI] [PubMed] [Google Scholar]
  41. Sherr C. J. G1 phase progression: cycling on cue. Cell. 1994 Nov 18;79(4):551–555. doi: 10.1016/0092-8674(94)90540-1. [DOI] [PubMed] [Google Scholar]
  42. Shi L., Nishioka W. K., Th'ng J., Bradbury E. M., Litchfield D. W., Greenberg A. H. Premature p34cdc2 activation required for apoptosis. Science. 1994 Feb 25;263(5150):1143–1145. doi: 10.1126/science.8108732. [DOI] [PubMed] [Google Scholar]
  43. Spitkovsky D., Steiner P., Gopalkrishnan R. V., Eilers M., Jansen-Dürr P. The role of p53 in coordinated regulation of cyclin D1 and p21 gene expression by the adenovirus E1A and E1B oncogenes. Oncogene. 1995 Jun 15;10(12):2421–2425. [PubMed] [Google Scholar]
  44. Spitkovsky D., Steiner P., Lukas J., Lees E., Pagano M., Schulze A., Joswig S., Picard D., Tommasino M., Eilers M. Modulation of cyclin gene expression by adenovirus E1A in a cell line with E1A-dependent conditional proliferation. J Virol. 1994 Apr;68(4):2206–2214. doi: 10.1128/jvi.68.4.2206-2214.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Tam S. W., Shay J. W., Pagano M. Differential expression and cell cycle regulation of the cyclin-dependent kinase 4 inhibitor p16Ink4. Cancer Res. 1994 Nov 15;54(22):5816–5820. [PubMed] [Google Scholar]
  46. Wang T. C., Cardiff R. D., Zukerberg L., Lees E., Arnold A., Schmidt E. V. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature. 1994 Jun 23;369(6482):669–671. doi: 10.1038/369669a0. [DOI] [PubMed] [Google Scholar]
  47. Withers D. A., Harvey R. C., Faust J. B., Melnyk O., Carey K., Meeker T. C. Characterization of a candidate bcl-1 gene. Mol Cell Biol. 1991 Oct;11(10):4846–4853. doi: 10.1128/mcb.11.10.4846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Xiong Y., Connolly T., Futcher B., Beach D. Human D-type cyclin. Cell. 1991 May 17;65(4):691–699. doi: 10.1016/0092-8674(91)90100-d. [DOI] [PubMed] [Google Scholar]
  49. Xiong Y., Zhang H., Beach D. Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation. Genes Dev. 1993 Aug;7(8):1572–1583. doi: 10.1101/gad.7.8.1572. [DOI] [PubMed] [Google Scholar]
  50. van Dam H., Offringa R., Meijer I., Stein B., Smits A. M., Herrlich P., Bos J. L., van der Eb A. J. Differential effects of the adenovirus E1A oncogene on members of the AP-1 transcription factor family. Mol Cell Biol. 1990 Nov;10(11):5857–5864. doi: 10.1128/mcb.10.11.5857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. van Dam H., Offringa R., Smits A. M., Bos J. L., Jones N. C., van der Eb A. J. The repression of the growth factor-inducible genes JE, c-myc and stromelysin by adenovirus E1A is mediated by conserved region 1. Oncogene. 1989 Oct;4(10):1207–1212. [PubMed] [Google Scholar]
  52. van der Eb A. J., Graham F. L. Assay of transforming activity of tumor virus DNA. Methods Enzymol. 1980;65(1):826–839. doi: 10.1016/s0076-6879(80)65077-0. [DOI] [PubMed] [Google Scholar]

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