Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 1997 Aug 15;326(Pt 1):61–68. doi: 10.1042/bj3260061

Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase.

J D Weber 1, D M Raben 1, P J Phillips 1, J J Baldassare 1
PMCID: PMC1218637  PMID: 9337851

Abstract

In Chinese hamster embryo fibroblasts (IIC9 cells), platelet-derived growth factor (PDGF) stimulated mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAP kinase/ERK) activity, but not that of c-jun N-terminal kinase (JNK), and induced G1 phase progression. ERK1 activation was biphasic and was sustained throughout the G1 phase of the cell cycle. PDGF induced cyclin D1 protein and mRNA levels in a time-dependent manner. Inhibition of PDGF-induced ERK1 activity by the addition of a selective inhibitor of MEK1 (MAP kinase kinase/ERK kinase 1) activation, PD98059, or transfection with a dominant-negative ERK1 (dnERK-) was correlated with growth arrest. In contrast, growth was unaffected by expression of dominant-negative JNK (dnJNK-). Interestingly, addition of PD98059 or dnERK-, but not dnJNK-, resulted in a dramatic decrease in cyclin D1 protein and mRNA levels, concomitant with a decrease in cyclin D1-cyclin-dependent kinase activity. To investigate the importance of sustained ERK1 activation, ERK1 activity was blocked by the addition of PD98059 throughout G1. Addition of PD98059 up to 4 h after PDGF treatment decreased ERK1 activity to the levels found in growth-arrested IIC9 cells. Loss of cyclin D1 mRNA and protein expression was observed within 1 h after inhibition of the second sustained phase of ERK1 activity. Disruption of sustained ERK1 activity also resulted in G1 growth arrest. These data provide evidence for a role for sustained ERK activity in controlling G1 progression through positive regulation of the continued expression of cyclin D1, a protein known to positively regulate G1 progression.

Full Text

The Full Text of this article is available as a PDF (340.6 KB).

Selected References

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

  1. Albanese C., Johnson J., Watanabe G., Eklund N., Vu D., Arnold A., Pestell R. G. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem. 1995 Oct 6;270(40):23589–23597. doi: 10.1074/jbc.270.40.23589. [DOI] [PubMed] [Google Scholar]
  2. Alessi D. R., Cuenda A., Cohen P., Dudley D. T., Saltiel A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995 Nov 17;270(46):27489–27494. doi: 10.1074/jbc.270.46.27489. [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. 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]
  6. 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]
  7. Graña X., Reddy E. P. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene. 1995 Jul 20;11(2):211–219. [PubMed] [Google Scholar]
  8. Hatakeyama M., Brill J. A., Fink G. R., Weinberg R. A. Collaboration of G1 cyclins in the functional inactivation of the retinoblastoma protein. Genes Dev. 1994 Aug 1;8(15):1759–1771. doi: 10.1101/gad.8.15.1759. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. 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]
  12. Lavoie J. N., L'Allemain G., Brunet A., Müller R., Pouysségur J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem. 1996 Aug 23;271(34):20608–20616. doi: 10.1074/jbc.271.34.20608. [DOI] [PubMed] [Google Scholar]
  13. Liu J. J., Chao J. R., Jiang M. C., Ng S. Y., Yen J. J., Yang-Yen H. F. Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol Cell Biol. 1995 Jul;15(7):3654–3663. doi: 10.1128/mcb.15.7.3654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Low D. A., Scott R. W., Baker J. B., Cunningham D. D. Cells regulate their mitogenic response to thrombin through release of protease nexin. Nature. 1982 Jul 29;298(5873):476–478. doi: 10.1038/298476a0. [DOI] [PubMed] [Google Scholar]
  15. Lukas J., Bartkova J., Welcker M., Petersen O. W., Peters G., Strauss M., Bartek J. Cyclin D2 is a moderately oscillating nucleoprotein required for G1 phase progression in specific cell types. Oncogene. 1995 Jun 1;10(11):2125–2134. [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. Resnitzky D., Reed S. I. Different roles for cyclins D1 and E in regulation of the G1-to-S transition. Mol Cell Biol. 1995 Jul;15(7):3463–3469. doi: 10.1128/mcb.15.7.3463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Reuter C. W., Catling A. D., Jelinek T., Weber M. J. Biochemical analysis of MEK activation in NIH3T3 fibroblasts. Identification of B-Raf and other activators. J Biol Chem. 1995 Mar 31;270(13):7644–7655. doi: 10.1074/jbc.270.13.7644. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Sherr C. J., Roberts J. M. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev. 1995 May 15;9(10):1149–1163. doi: 10.1101/gad.9.10.1149. [DOI] [PubMed] [Google Scholar]
  26. Vouret-Craviari V., Van Obberghen-Schilling E., Scimeca J. C., Van Obberghen E., Pouysségur J. Differential activation of p44mapk (ERK1) by alpha-thrombin and thrombin-receptor peptide agonist. Biochem J. 1993 Jan 1;289(Pt 1):209–214. doi: 10.1042/bj2890209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Winston J. T., Coats S. R., Wang Y. Z., Pledger W. J. Regulation of the cell cycle machinery by oncogenic ras. Oncogene. 1996 Jan 4;12(1):127–134. [PubMed] [Google Scholar]
  28. 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]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES