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. 1996 May;70(5):2911–2921. doi: 10.1128/jvi.70.5.2911-2921.1996

Cyclin-dependent kinases phosphorylate the adenovirus E1A protein, enhancing its ability to bind pRb and disrupt pRb-E2F complexes.

A Mal 1, A Piotrkowski 1, M L Harter 1
PMCID: PMC190149  PMID: 8627766

Abstract

The adenovirus E1A protein of 243 amino acids has been shown to affect a variety of cellular functions, most notably the immortalization of primary cells and the promotion of quiescent cells into S phase. The activity of E1A is derived, in part, from its association with various cellular proteins, many of which play important roles in regulating cell cycle progression. E1A is known to have multiple sites of phosphorylation. It has been suggested that cell cycle-dependent phosphorylation may also control some of E1A's functions. We find now that immune complexes of cyclin-dependent kinases such as cdk4, cdk2, and cdc2 are all capable of phosphorylating E1A in vitro. Additionally, the sites on E1A phosphorylated by these kinases in vitro are similar to the E1A sites phosphorylated in vivo. We have also found that a phosphorylated E1A is far more efficient than an unphosphorylated E1A in associating with pRB and in disrupting E2F/DP-pRB complexes as well. On the basis of our findings and the differences in timing and expression levels of the various cyclins regulating cdks, we suggest that E1A functions at different control points in the cell cycle and that phosphorylation controls, to some extent, its biological functions.

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Selected References

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  1. Abraham S. E., Lobo S., Yaciuk P., Wang H. G., Moran E. p300, and p300-associated proteins, are components of TATA-binding protein (TBP) complexes. Oncogene. 1993 Jun;8(6):1639–1647. [PubMed] [Google Scholar]
  2. Ando K., Ajchenbaum-Cymbalista F., Griffin J. D. Regulation of G1/S transition by cyclins D2 and D3 in hematopoietic cells. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9571–9575. doi: 10.1073/pnas.90.20.9571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arany Z., Newsome D., Oldread E., Livingston D. M., Eckner R. A family of transcriptional adaptor proteins targeted by the E1A oncoprotein. Nature. 1995 Mar 2;374(6517):81–84. doi: 10.1038/374081a0. [DOI] [PubMed] [Google Scholar]
  4. Baeuerle P. A., Baltimore D. Activation of DNA-binding activity in an apparently cytoplasmic precursor of the NF-kappa B transcription factor. Cell. 1988 Apr 22;53(2):211–217. doi: 10.1016/0092-8674(88)90382-0. [DOI] [PubMed] [Google Scholar]
  5. Bagchi S., Raychaudhuri P., Nevins J. R. Adenovirus E1A proteins can dissociate heteromeric complexes involving the E2F transcription factor: a novel mechanism for E1A trans-activation. Cell. 1990 Aug 24;62(4):659–669. doi: 10.1016/0092-8674(90)90112-r. [DOI] [PubMed] [Google Scholar]
  6. Banerjee A. C., Recupero A. J., Mal A., Piotrkowski A. M., Wang D. M., Harter M. L. The adenovirus E1A 289R and 243R proteins inhibit the phosphorylation of p300. Oncogene. 1994 Jun;9(6):1733–1737. [PubMed] [Google Scholar]
  7. Barbeau D., Charbonneau R., Whalen S. G., Bayley S. T., Branton P. E. Functional interactions within adenovirus E1A protein complexes. Oncogene. 1994 Feb;9(2):359–373. [PubMed] [Google Scholar]
  8. Barik S. Expression and biochemical properties of a protein serine/threonine phosphatase encoded by bacteriophage lambda. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10633–10637. doi: 10.1073/pnas.90.22.10633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Beijersbergen R. L., Carlée L., Kerkhoven R. M., Bernards R. Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes. Genes Dev. 1995 Jun 1;9(11):1340–1353. doi: 10.1101/gad.9.11.1340. [DOI] [PubMed] [Google Scholar]
  10. Buchkovich K., Duffy L. A., Harlow E. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell. 1989 Sep 22;58(6):1097–1105. doi: 10.1016/0092-8674(89)90508-4. [DOI] [PubMed] [Google Scholar]
  11. Caruso M., Martelli F., Giordano A., Felsani A. Regulation of MyoD gene transcription and protein function by the transforming domains of the adenovirus E1A oncoprotein. Oncogene. 1993 Feb;8(2):267–278. [PubMed] [Google Scholar]
  12. Chatterjee P. K., Flint S. J. Partition of E1A proteins between soluble and structural fractions of adenovirus-infected and -transformed cells. J Virol. 1986 Dec;60(3):1018–1026. doi: 10.1128/jvi.60.3.1018-1026.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chellappan S. P., Hiebert S., Mudryj M., Horowitz J. M., Nevins J. R. The E2F transcription factor is a cellular target for the RB protein. Cell. 1991 Jun 14;65(6):1053–1061. doi: 10.1016/0092-8674(91)90557-f. [DOI] [PubMed] [Google Scholar]
  14. Claudio P. P., Howard C. M., Baldi A., De Luca A., Fu Y., Condorelli G., Sun Y., Colburn N., Calabretta B., Giordano A. p130/pRb2 has growth suppressive properties similar to yet distinctive from those of retinoblastoma family members pRb and p107. Cancer Res. 1994 Nov 1;54(21):5556–5560. [PubMed] [Google Scholar]
  15. Cleveland D. W., Fischer S. G., Kirschner M. W., Laemmli U. K. Peptide mapping by limited proteolysis in sodium dodecyl sulfate and analysis by gel electrophoresis. J Biol Chem. 1977 Feb 10;252(3):1102–1106. [PubMed] [Google Scholar]
  16. Cobrinik D., Whyte P., Peeper D. S., Jacks T., Weinberg R. A. Cell cycle-specific association of E2F with the p130 E1A-binding protein. Genes Dev. 1993 Dec;7(12A):2392–2404. doi: 10.1101/gad.7.12a.2392. [DOI] [PubMed] [Google Scholar]
  17. Datta S., Soong C. J., Wang D. M., Harter M. L. A purified adenovirus 289-amino-acid E1A protein activates RNA polymerase III transcription in vitro and alters transcription factor TFIIIC. J Virol. 1991 Oct;65(10):5297–5304. doi: 10.1128/jvi.65.10.5297-5304.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dobrowolski S. F., Stacey D. W., Harter M. L., Stine J. T., Hiebert S. W. An E2F dominant negative mutant blocks E1A induced cell cycle progression. Oncogene. 1994 Sep;9(9):2605–2612. [PubMed] [Google Scholar]
  19. Dobrowolski S., Harter M., Stacey D. W. Cellular ras activity is required for passage through multiple points of the G0/G1 phase in BALB/c 3T3 cells. Mol Cell Biol. 1994 Aug;14(8):5441–5449. doi: 10.1128/mcb.14.8.5441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Dou Q. P., Levin A. H., Zhao S., Pardee A. B. Cyclin E and cyclin A as candidates for the restriction point protein. Cancer Res. 1993 Apr 1;53(7):1493–1497. [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. Dumont D. J., Branton P. E. Phosphorylation of adenovirus E1A proteins by the p34cdc2 protein kinase. Virology. 1992 Jul;189(1):111–120. doi: 10.1016/0042-6822(92)90686-j. [DOI] [PubMed] [Google Scholar]
  24. Dumont D. J., Marcellus R. C., Bayley S. T., Branton P. E. Role of phosphorylation near the amino terminus of adenovirus type 5 early region 1A proteins. J Gen Virol. 1993 Apr;74(Pt 4):583–595. doi: 10.1099/0022-1317-74-4-583. [DOI] [PubMed] [Google Scholar]
  25. Dynlacht B. D., Flores O., Lees J. A., Harlow E. Differential regulation of E2F transactivation by cyclin/cdk2 complexes. Genes Dev. 1994 Aug 1;8(15):1772–1786. doi: 10.1101/gad.8.15.1772. [DOI] [PubMed] [Google Scholar]
  26. Dyson N., Buchkovich K., Whyte P., Harlow E. The cellular 107K protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus. Cell. 1989 Jul 28;58(2):249–255. doi: 10.1016/0092-8674(89)90839-8. [DOI] [PubMed] [Google Scholar]
  27. Dyson N., Guida P., McCall C., Harlow E. Adenovirus E1A makes two distinct contacts with the retinoblastoma protein. J Virol. 1992 Jul;66(7):4606–4611. doi: 10.1128/jvi.66.7.4606-4611.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Dyson N., Harlow E. Adenovirus E1A targets key regulators of cell proliferation. Cancer Surv. 1992;12:161–195. [PubMed] [Google Scholar]
  29. Engström L., Ekman P., Humble E., Ragnarsson U., Zetterqvist O. Detection and identification of substrates for protein kinases: use of proteins and synthetic peptides. Methods Enzymol. 1984;107:130–154. doi: 10.1016/0076-6879(84)07008-7. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Ewen M. E., Xing Y. G., Lawrence J. B., Livingston D. M. Molecular cloning, chromosomal mapping, and expression of the cDNA for p107, a retinoblastoma gene product-related protein. Cell. 1991 Sep 20;66(6):1155–1164. doi: 10.1016/0092-8674(91)90038-z. [DOI] [PubMed] [Google Scholar]
  32. Faha B., Ewen M. E., Tsai L. H., Livingston D. M., Harlow E. Interaction between human cyclin A and adenovirus E1A-associated p107 protein. Science. 1992 Jan 3;255(5040):87–90. doi: 10.1126/science.1532458. [DOI] [PubMed] [Google Scholar]
  33. Faha B., Harlow E., Lees E. The adenovirus E1A-associated kinase consists of cyclin E-p33cdk2 and cyclin A-p33cdk2. J Virol. 1993 May;67(5):2456–2465. doi: 10.1128/jvi.67.5.2456-2465.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Fanning E. Simian virus 40 large T antigen: the puzzle, the pieces, and the emerging picture. J Virol. 1992 Mar;66(3):1289–1293. doi: 10.1128/jvi.66.3.1289-1293.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Fattaey A. R., Harlow E., Helin K. Independent regions of adenovirus E1A are required for binding to and dissociation of E2F-protein complexes. Mol Cell Biol. 1993 Dec;13(12):7267–7277. doi: 10.1128/mcb.13.12.7267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Fischer S. G. Peptide mapping in gels. Methods Enzymol. 1983;100:424–430. doi: 10.1016/0076-6879(83)00071-3. [DOI] [PubMed] [Google Scholar]
  37. Giordano A., Whyte P., Harlow E., Franza B. R., Jr, Beach D., Draetta G. A 60 kd cdc2-associated polypeptide complexes with the E1A proteins in adenovirus-infected cells. Cell. 1989 Sep 8;58(5):981–990. doi: 10.1016/0092-8674(89)90949-5. [DOI] [PubMed] [Google Scholar]
  38. Graham F. L., Smiley J., Russell W. C., Nairn R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol. 1977 Jul;36(1):59–74. doi: 10.1099/0022-1317-36-1-59. [DOI] [PubMed] [Google Scholar]
  39. Harlow E., Franza B. R., Jr, Schley C. Monoclonal antibodies specific for adenovirus early region 1A proteins: extensive heterogeneity in early region 1A products. J Virol. 1985 Sep;55(3):533–546. doi: 10.1128/jvi.55.3.533-546.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Harlow E., Whyte P., Franza B. R., Jr, Schley C. Association of adenovirus early-region 1A proteins with cellular polypeptides. Mol Cell Biol. 1986 May;6(5):1579–1589. doi: 10.1128/mcb.6.5.1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Harter M. L., Lewis J. B. Adenovirus type 2 early proteins synthesized in vitro and in vivo: identification in infected cells of the 38,000- to 50,000- molecular-weight protein encoded by the left end of the adenovirus type 2 genome. J Virol. 1978 Jun;26(3):736–749. doi: 10.1128/jvi.26.3.736-749.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Helin K., Harlow E., Fattaey A. Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein. Mol Cell Biol. 1993 Oct;13(10):6501–6508. doi: 10.1128/mcb.13.10.6501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Helin K., Wu C. L., Fattaey A. R., Lees J. A., Dynlacht B. D., Ngwu C., Harlow E. Heterodimerization of the transcription factors E2F-1 and DP-1 leads to cooperative trans-activation. Genes Dev. 1993 Oct;7(10):1850–1861. doi: 10.1101/gad.7.10.1850. [DOI] [PubMed] [Google Scholar]
  44. Hepler P. K., Sek F. J., John P. C. Nuclear concentration and mitotic dispersion of the essential cell cycle protein, p13suc1, examined in living cells. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2176–2180. doi: 10.1073/pnas.91.6.2176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. 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]
  46. Horton L. E., Qian Y., Templeton D. J. G1 cyclins control the retinoblastoma gene product growth regulation activity via upstream mechanisms. Cell Growth Differ. 1995 Apr;6(4):395–407. [PubMed] [Google Scholar]
  47. Howe J. A., Mymryk J. S., Egan C., Branton P. E., Bayley S. T. Retinoblastoma growth suppressor and a 300-kDa protein appear to regulate cellular DNA synthesis. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5883–5887. doi: 10.1073/pnas.87.15.5883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Howe P. H., Draetta G., Leof E. B. Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest. Mol Cell Biol. 1991 Mar;11(3):1185–1194. doi: 10.1128/mcb.11.3.1185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Hu Q. J., Dyson N., Harlow E. The regions of the retinoblastoma protein needed for binding to adenovirus E1A or SV40 large T antigen are common sites for mutations. EMBO J. 1990 Apr;9(4):1147–1155. doi: 10.1002/j.1460-2075.1990.tb08221.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Hunter T. Braking the cycle. Cell. 1993 Dec 3;75(5):839–841. doi: 10.1016/0092-8674(93)90528-x. [DOI] [PubMed] [Google Scholar]
  51. Hunter T., Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age. Cell. 1994 Nov 18;79(4):573–582. doi: 10.1016/0092-8674(94)90543-6. [DOI] [PubMed] [Google Scholar]
  52. Ikeda M. A., Nevins J. R. Identification of distinct roles for separate E1A domains in disruption of E2F complexes. Mol Cell Biol. 1993 Nov;13(11):7029–7035. doi: 10.1128/mcb.13.11.7029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Kaelin W. G., Jr, Ewen M. E., Livingston D. M. Definition of the minimal simian virus 40 large T antigen- and adenovirus E1A-binding domain in the retinoblastoma gene product. Mol Cell Biol. 1990 Jul;10(7):3761–3769. doi: 10.1128/mcb.10.7.3761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Kato J. Y., Matsuoka M., Strom D. K., Sherr C. J. Regulation of cyclin D-dependent kinase 4 (cdk4) by cdk4-activating kinase. Mol Cell Biol. 1994 Apr;14(4):2713–2721. doi: 10.1128/mcb.14.4.2713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. 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]
  56. Kitagawa M., Higashi H., Suzuki-Takahashi I., Segawa K., Hanks S. K., Taya Y., Nishimura S., Okuyama A. Phosphorylation of E2F-1 by cyclin A-cdk2. Oncogene. 1995 Jan 19;10(2):229–236. [PubMed] [Google Scholar]
  57. Kleinberger T., Shenk T. A protein kinase is present in a complex with adenovirus E1A proteins. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11143–11147. doi: 10.1073/pnas.88.24.11143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. 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]
  59. Krek W., Ewen M. E., Shirodkar S., Arany Z., Kaelin W. G., Jr, Livingston D. M. Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell. 1994 Jul 15;78(1):161–172. doi: 10.1016/0092-8674(94)90582-7. [DOI] [PubMed] [Google Scholar]
  60. La Thangue N. B. DRTF1/E2F: an expanding family of heterodimeric transcription factors implicated in cell-cycle control. Trends Biochem Sci. 1994 Mar;19(3):108–114. doi: 10.1016/0968-0004(94)90202-x. [DOI] [PubMed] [Google Scholar]
  61. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  62. Lee J. S., Galvin K. M., See R. H., Eckner R., Livingston D., Moran E., Shi Y. Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300. Genes Dev. 1995 May 15;9(10):1188–1198. doi: 10.1101/gad.9.10.1188. [DOI] [PubMed] [Google Scholar]
  63. Lees E., Faha B., Dulic V., Reed S. I., Harlow E. Cyclin E/cdk2 and cyclin A/cdk2 kinases associate with p107 and E2F in a temporally distinct manner. Genes Dev. 1992 Oct;6(10):1874–1885. doi: 10.1101/gad.6.10.1874. [DOI] [PubMed] [Google Scholar]
  64. Li Y., Graham C., Lacy S., Duncan A. M., Whyte P. The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. Genes Dev. 1993 Dec;7(12A):2366–2377. doi: 10.1101/gad.7.12a.2366. [DOI] [PubMed] [Google Scholar]
  65. Lucher L. A., Loewenstein P. M., Green M. Phosphorylation in vitro of Escherichia coli-produced 235R and 266R tumor antigens encoded by human adenovirus type 12 early transformation region 1A. J Virol. 1985 Oct;56(1):183–193. doi: 10.1128/jvi.56.1.183-193.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Ludlow J. W., Skuse G. R. Viral oncoprotein binding to pRB, p107, p130, and p300. Virus Res. 1995 Feb;35(2):113–121. doi: 10.1016/0168-1702(94)00094-s. [DOI] [PubMed] [Google Scholar]
  67. Lundblad J. R., Kwok R. P., Laurance M. E., Harter M. L., Goodman R. H. Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP. Nature. 1995 Mar 2;374(6517):85–88. doi: 10.1038/374085a0. [DOI] [PubMed] [Google Scholar]
  68. 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]
  69. 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]
  70. McVey D., Brizuela L., Mohr I., Marshak D. R., Gluzman Y., Beach D. Phosphorylation of large tumour antigen by cdc2 stimulates SV40 DNA replication. Nature. 1989 Oct 12;341(6242):503–507. doi: 10.1038/341503a0. [DOI] [PubMed] [Google Scholar]
  71. Meyerson M., Enders G. H., Wu C. L., Su L. K., Gorka C., Nelson C., Harlow E., Tsai L. H. A family of human cdc2-related protein kinases. EMBO J. 1992 Aug;11(8):2909–2917. doi: 10.1002/j.1460-2075.1992.tb05360.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. 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]
  73. Missero C., Filvaroff E., Dotto G. P. Induction of transforming growth factor beta 1 resistance by the E1A oncogene requires binding to a specific set of cellular proteins. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3489–3493. doi: 10.1073/pnas.88.8.3489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Moodie S. A., Willumsen B. M., Weber M. J., Wolfman A. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science. 1993 Jun 11;260(5114):1658–1661. doi: 10.1126/science.8503013. [DOI] [PubMed] [Google Scholar]
  75. Müller R., Mumberg D., Lucibello F. C. Signals and genes in the control of cell-cycle progression. Biochim Biophys Acta. 1993 Aug 23;1155(2):151–179. doi: 10.1016/0304-419x(93)90003-u. [DOI] [PubMed] [Google Scholar]
  76. Müller R. Transcriptional regulation during the mammalian cell cycle. Trends Genet. 1995 May;11(5):173–178. doi: 10.1016/S0168-9525(00)89039-3. [DOI] [PubMed] [Google Scholar]
  77. Nevins J. R. Disruption of cell-cycle control by viral oncoproteins. Biochem Soc Trans. 1993 Nov;21(4):935–938. doi: 10.1042/bst0210935. [DOI] [PubMed] [Google Scholar]
  78. 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]
  79. Pagano M., Pepperkok R., Verde F., Ansorge W., Draetta G. Cyclin A is required at two points in the human cell cycle. EMBO J. 1992 Mar;11(3):961–971. doi: 10.1002/j.1460-2075.1992.tb05135.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Pines J., Hunter T. Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B. Nature. 1990 Aug 23;346(6286):760–763. doi: 10.1038/346760a0. [DOI] [PubMed] [Google Scholar]
  81. Pines J., Hunter T. p34cdc2: the S and M kinase? New Biol. 1990 May;2(5):389–401. [PubMed] [Google Scholar]
  82. Poon R. Y., Yamashita K., Adamczewski J. P., Hunt T., Shuttleworth J. The cdc2-related protein p40MO15 is the catalytic subunit of a protein kinase that can activate p33cdk2 and p34cdc2. EMBO J. 1993 Aug;12(8):3123–3132. doi: 10.1002/j.1460-2075.1993.tb05981.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Poon R. Y., Yamashita K., Howell M., Ershler M. A., Belyavsky A., Hunt T. Cell cycle regulation of the p34cdc2/p33cdk2-activating kinase p40MO15. J Cell Sci. 1994 Oct;107(Pt 10):2789–2799. doi: 10.1242/jcs.107.10.2789. [DOI] [PubMed] [Google Scholar]
  84. 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]
  85. Rao L., Debbas M., Sabbatini P., Hockenbery D., Korsmeyer S., White E. The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7742–7746. doi: 10.1073/pnas.89.16.7742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Raychaudhuri P., Bagchi S., Devoto S. H., Kraus V. B., Moran E., Nevins J. R. Domains of the adenovirus E1A protein required for oncogenic activity are also required for dissociation of E2F transcription factor complexes. Genes Dev. 1991 Jul;5(7):1200–1211. doi: 10.1101/gad.5.7.1200. [DOI] [PubMed] [Google Scholar]
  87. Richter J. D., Slavicek J. M., Schneider J. F., Jones N. C. Heterogeneity of adenovirus type 5 E1A proteins: multiple serine phosphorylations induce slow-migrating electrophoretic variants but do not affect E1A-induced transcriptional activation or transformation. J Virol. 1988 Jun;62(6):1948–1955. doi: 10.1128/jvi.62.6.1948-1955.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Roach P. J. Multisite and hierarchal protein phosphorylation. J Biol Chem. 1991 Aug 5;266(22):14139–14142. [PubMed] [Google Scholar]
  89. Rosenblatt J., Gu Y., Morgan D. O. Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2824–2828. doi: 10.1073/pnas.89.7.2824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Ruderman J. V. MAP kinase and the activation of quiescent cells. Curr Opin Cell Biol. 1993 Apr;5(2):207–213. doi: 10.1016/0955-0674(93)90104-x. [DOI] [PubMed] [Google Scholar]
  91. Russo G. L., Vandenberg M. T., Yu I. J., Bae Y. S., Franza B. R., Jr, Marshak D. R. Casein kinase II phosphorylates p34cdc2 kinase in G1 phase of the HeLa cell division cycle. J Biol Chem. 1992 Oct 5;267(28):20317–20325. [PubMed] [Google Scholar]
  92. Schwarz J. K., Devoto S. H., Smith E. J., Chellappan S. P., Jakoi L., Nevins J. R. Interactions of the p107 and Rb proteins with E2F during the cell proliferation response. EMBO J. 1993 Mar;12(3):1013–1020. doi: 10.1002/j.1460-2075.1993.tb05742.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Shenk T., Flint J. Transcriptional and transforming activities of the adenovirus E1A proteins. Adv Cancer Res. 1991;57:47–85. doi: 10.1016/s0065-230x(08)60995-1. [DOI] [PubMed] [Google Scholar]
  94. Sherr C. J. D-type cyclins. Trends Biochem Sci. 1995 May;20(5):187–190. doi: 10.1016/s0968-0004(00)89005-2. [DOI] [PubMed] [Google Scholar]
  95. 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]
  96. Sherr C. J. Mammalian G1 cyclins. Cell. 1993 Jun 18;73(6):1059–1065. doi: 10.1016/0092-8674(93)90636-5. [DOI] [PubMed] [Google Scholar]
  97. Smith C. L., Debouck C., Rosenberg M., Culp J. S. Phosphorylation of serine residue 89 of human adenovirus E1A proteins is responsible for their characteristic electrophoretic mobility shifts, and its mutation affects biological function. J Virol. 1989 Apr;63(4):1569–1577. doi: 10.1128/jvi.63.4.1569-1577.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Smith D. H., Ziff E. B. The amino-terminal region of the adenovirus serotype 5 E1a protein performs two separate functions when expressed in primary baby rat kidney cells. Mol Cell Biol. 1988 Sep;8(9):3882–3890. doi: 10.1128/mcb.8.9.3882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Stabel S., Argos P., Philipson L. The release of growth arrest by microinjection of adenovirus E1A DNA. EMBO J. 1985 Sep;4(9):2329–2336. doi: 10.1002/j.1460-2075.1985.tb03934.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Stacey D. W., Dobrowolski S. F., Piotrkowski A., Harter M. L. The adenovirus E1A protein overrides the requirement for cellular ras in initiating DNA synthesis. EMBO J. 1994 Dec 15;13(24):6107–6114. doi: 10.1002/j.1460-2075.1994.tb06957.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Tremblay M. L., Dumont D. J., Branton P. E. Analysis of phosphorylation sites in the exon 1 region of E1A proteins of human adenovirus type 5. Virology. 1989 Apr;169(2):397–407. doi: 10.1016/0042-6822(89)90165-7. [DOI] [PubMed] [Google Scholar]
  102. Tremblay M. L., McGlade C. J., Gerber G. E., Branton P. E. Identification of the phosphorylation sites in early region 1A proteins of adenovirus type 5 by amino acid sequencing of peptide fragments. J Biol Chem. 1988 May 5;263(13):6375–6383. [PubMed] [Google Scholar]
  103. Vindeløv L. L., Christensen I. J., Nissen N. I. A detergent-trypsin method for the preparation of nuclei for flow cytometric DNA analysis. Cytometry. 1983 Mar;3(5):323–327. doi: 10.1002/cyto.990030503. [DOI] [PubMed] [Google Scholar]
  104. Wang D. M., Dalie B., Harter M. L. The adenovirus E1A 243R protein purified from Escherichia coli under nondenaturing conditions is found in association with dnaK. Protein Expr Purif. 1992 Feb;3(1):8–17. doi: 10.1016/1046-5928(92)90050-7. [DOI] [PubMed] [Google Scholar]
  105. Wang H. G., Rikitake Y., Carter M. C., Yaciuk P., Abraham S. E., Zerler B., Moran E. Identification of specific adenovirus E1A N-terminal residues critical to the binding of cellular proteins and to the control of cell growth. J Virol. 1993 Jan;67(1):476–488. doi: 10.1128/jvi.67.1.476-488.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Webster K. A., Muscat G. E., Kedes L. Adenovirus E1A products suppress myogenic differentiation and inhibit transcription from muscle-specific promoters. Nature. 1988 Apr 7;332(6164):553–557. doi: 10.1038/332553a0. [DOI] [PubMed] [Google Scholar]
  107. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  108. Welch P. J., Wang J. Y. Coordinated synthesis and degradation of cdc2 in the mammalian cell cycle. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3093–3097. doi: 10.1073/pnas.89.7.3093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Whyte P., Buchkovich K. J., Horowitz J. M., Friend S. H., Raybuck M., Weinberg R. A., Harlow E. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature. 1988 Jul 14;334(6178):124–129. doi: 10.1038/334124a0. [DOI] [PubMed] [Google Scholar]
  110. Wu C. L., Zukerberg L. R., Ngwu C., Harlow E., Lees J. A. In vivo association of E2F and DP family proteins. Mol Cell Biol. 1995 May;15(5):2536–2546. doi: 10.1128/mcb.15.5.2536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. 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]
  112. 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]
  113. Yaciuk P., Moran E. Analysis with specific polyclonal antiserum indicates that the E1A-associated 300-kDa product is a stable nuclear phosphoprotein that undergoes cell cycle phase-specific modification. Mol Cell Biol. 1991 Nov;11(11):5389–5397. doi: 10.1128/mcb.11.11.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Yee S. P., Branton P. E. Detection of cellular proteins associated with human adenovirus type 5 early region 1A polypeptides. Virology. 1985 Nov;147(1):142–153. doi: 10.1016/0042-6822(85)90234-x. [DOI] [PubMed] [Google Scholar]
  115. Yee S. P., Rowe D. T., Tremblay M. L., McDermott M., Branton P. E. Identification of human adenovirus early region 1 products by using antisera against synthetic peptides corresponding to the predicted carboxy termini. J Virol. 1983 Jun;46(3):1003–1013. doi: 10.1128/jvi.46.3.1003-1013.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Yu I. J., Spector D. L., Bae Y. S., Marshak D. R. Immunocytochemical localization of casein kinase II during interphase and mitosis. J Cell Biol. 1991 Sep;114(6):1217–1232. doi: 10.1083/jcb.114.6.1217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Zhu L., van den Heuvel S., Helin K., Fattaey A., Ewen M., Livingston D., Dyson N., Harlow E. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein. Genes Dev. 1993 Jul;7(7A):1111–1125. doi: 10.1101/gad.7.7a.1111. [DOI] [PubMed] [Google Scholar]

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