Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Sep;17(9):5588–5597. doi: 10.1128/mcb.17.9.5588

High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1.

A Sewing 1, B Wiseman 1, A C Lloyd 1, H Land 1
PMCID: PMC232407  PMID: 9271434

Abstract

Activated Raf has been linked to such opposing cellular responses as the induction of DNA synthesis and the inhibition of proliferation. However, it remains unclear how such a switch in signal specificity is regulated. We have addressed this question with a regulatable Raf-androgen receptor fusion protein in murine fibroblasts. We show that Raf can cause a G1-specific cell cycle arrest through induction of p21Cip1. This in turn leads to inhibition of cyclin D- and cyclin E-dependent kinases and an accumulation of hypophosphorylated Rb. Importantly, this behavior can be observed only in response to a strong Raf signal. In contrast, moderate Raf activity induces DNA synthesis and is sufficient to induce cyclin D expression. Therefore, Raf signal specificity can be determined by modulation of signal strength presumably through the induction of distinct protein expression patterns. Similar to induction of Raf, a strong induction of activated Ras via a tetracycline-dependent promoter also causes inhibition of proliferation and p21Cip1 induction at high expression levels. Thus, p21Cip1 plays a key role in determining cellular responses to Ras and Raf signalling. As predicted by this finding we show that Ras and loss of p21 cooperate to confer a proliferative advantage to mouse embryo fibroblasts.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

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

  1. Ahn N. G., Seger R., Bratlien R. L., Diltz C. D., Tonks N. K., Krebs E. G. Multiple components in an epidermal growth factor-stimulated protein kinase cascade. In vitro activation of a myelin basic protein/microtubule-associated protein 2 kinase. J Biol Chem. 1991 Mar 5;266(7):4220–4227. [PubMed] [Google Scholar]
  2. Beck T. W., Huleihel M., Gunnell M., Bonner T. I., Rapp U. R. The complete coding sequence of the human A-raf-1 oncogene and transforming activity of a human A-raf carrying retrovirus. Nucleic Acids Res. 1987 Jan 26;15(2):595–609. doi: 10.1093/nar/15.2.595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blasi E., Mathieson B. J., Varesio L., Cleveland J. L., Borchert P. A., Rapp U. R. Selective immortalization of murine macrophages from fresh bone marrow by a raf/myc recombinant murine retrovirus. Nature. 1985 Dec 19;318(6047):667–670. doi: 10.1038/318667a0. [DOI] [PubMed] [Google Scholar]
  4. Brugarolas J., Chandrasekaran C., Gordon J. I., Beach D., Jacks T., Hannon G. J. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995 Oct 12;377(6549):552–557. doi: 10.1038/377552a0. [DOI] [PubMed] [Google Scholar]
  5. Brunner D., Oellers N., Szabad J., Biggs W. H., 3rd, Zipursky S. L., Hafen E. A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways. Cell. 1994 Mar 11;76(5):875–888. doi: 10.1016/0092-8674(94)90362-x. [DOI] [PubMed] [Google Scholar]
  6. Büscher D., Dello Sbarba P., Hipskind R. A., Rapp U. R., Stanley E. R., Baccarini M. v-raf confers CSF-1 independent growth to a macrophage cell line and leads to immediate early gene expression without MAP-kinase activation. Oncogene. 1993 Dec;8(12):3323–3332. [PubMed] [Google Scholar]
  7. Chang F., Herskowitz I. Identification of a gene necessary for cell cycle arrest by a negative growth factor of yeast: FAR1 is an inhibitor of a G1 cyclin, CLN2. Cell. 1990 Nov 30;63(5):999–1011. doi: 10.1016/0092-8674(90)90503-7. [DOI] [PubMed] [Google Scholar]
  8. Chen R. H., Sarnecki C., Blenis J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992 Mar;12(3):915–927. doi: 10.1128/mcb.12.3.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  10. Cowley S., Paterson H., Kemp P., Marshall C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994 Jun 17;77(6):841–852. doi: 10.1016/0092-8674(94)90133-3. [DOI] [PubMed] [Google Scholar]
  11. Dahmer M. K., Perlman R. L. Insulin and insulin-like growth factors stimulate deoxyribonucleic acid synthesis in PC12 pheochromocytoma cells. Endocrinology. 1988 May;122(5):2109–2113. doi: 10.1210/endo-122-5-2109. [DOI] [PubMed] [Google Scholar]
  12. Datto M. B., Li Y., Panus J. F., Howe D. J., Xiong Y., Wang X. F. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5545–5549. doi: 10.1073/pnas.92.12.5545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Decker S. J. Nerve growth factor-induced growth arrest and induction of p21Cip1/WAF1 in NIH-3T3 cells expressing TrkA. J Biol Chem. 1995 Dec 29;270(52):30841–30844. doi: 10.1074/jbc.270.52.30841. [DOI] [PubMed] [Google Scholar]
  14. Del Sal G., Murphy M., Ruaro E., Lazarevic D., Levine A. J., Schneider C. Cyclin D1 and p21/waf1 are both involved in p53 growth suppression. Oncogene. 1996 Jan 4;12(1):177–185. [PubMed] [Google Scholar]
  15. Deng C., Zhang P., Harper J. W., Elledge S. J., Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 1995 Aug 25;82(4):675–684. doi: 10.1016/0092-8674(95)90039-x. [DOI] [PubMed] [Google Scholar]
  16. Diaz-Benjumea F. J., Hafen E. The sevenless signalling cassette mediates Drosophila EGF receptor function during epidermal development. Development. 1994 Mar;120(3):569–578. doi: 10.1242/dev.120.3.569. [DOI] [PubMed] [Google Scholar]
  17. Dikic I., Schlessinger J., Lax I. PC12 cells overexpressing the insulin receptor undergo insulin-dependent neuronal differentiation. Curr Biol. 1994 Aug 1;4(8):702–708. doi: 10.1016/s0960-9822(00)00155-x. [DOI] [PubMed] [Google Scholar]
  18. Dotto G. P., Parada L. F., Weinberg R. A. Specific growth response of ras-transformed embryo fibroblasts to tumour promoters. Nature. 1985 Dec 5;318(6045):472–475. doi: 10.1038/318472a0. [DOI] [PubMed] [Google Scholar]
  19. Dulić V., Drullinger L. F., Lees E., Reed S. I., Stein G. H. Altered regulation of G1 cyclins in senescent human diploid fibroblasts: accumulation of inactive cyclin E-Cdk2 and cyclin D1-Cdk2 complexes. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11034–11038. doi: 10.1073/pnas.90.23.11034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Evan G. I., Lewis G. K., Ramsay G., Bishop J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. doi: 10.1128/mcb.5.12.3610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fantl V., Stamp G., Andrews A., Rosewell I., Dickson C. Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 1995 Oct 1;9(19):2364–2372. doi: 10.1101/gad.9.19.2364. [DOI] [PubMed] [Google Scholar]
  22. Freeman M. Cell determination strategies in the Drosophila eye. Development. 1997 Jan;124(2):261–270. doi: 10.1242/dev.124.2.261. [DOI] [PubMed] [Google Scholar]
  23. Graf T., von Weizsaecker F., Grieser S., Coll J., Stehelin D., Patschinsky T., Bister K., Bechade C., Calothy G., Leutz A. v-mil induces autocrine growth and enhanced tumorigenicity in v-myc-transformed avian macrophages. Cell. 1986 May 9;45(3):357–364. doi: 10.1016/0092-8674(86)90321-1. [DOI] [PubMed] [Google Scholar]
  24. Guo K., Wang J., Andrés V., Smith R. C., Walsh K. MyoD-induced expression of p21 inhibits cyclin-dependent kinase activity upon myocyte terminal differentiation. Mol Cell Biol. 1995 Jul;15(7):3823–3829. doi: 10.1128/mcb.15.7.3823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Harper J. W., Elledge S. J., Keyomarsi K., Dynlacht B., Tsai L. H., Zhang P., Dobrowolski S., Bai C., Connell-Crowley L., Swindell E. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell. 1995 Apr;6(4):387–400. doi: 10.1091/mbc.6.4.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Howe L. R., Leevers S. J., Gómez N., Nakielny S., Cohen P., Marshall C. J. Activation of the MAP kinase pathway by the protein kinase raf. Cell. 1992 Oct 16;71(2):335–342. doi: 10.1016/0092-8674(92)90361-f. [DOI] [PubMed] [Google Scholar]
  27. Huff K., End D., Guroff G. Nerve growth factor-induced alteration in the response of PC12 pheochromocytoma cells to epidermal growth factor. J Cell Biol. 1981 Jan;88(1):189–198. doi: 10.1083/jcb.88.1.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hunter T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell. 1995 Jan 27;80(2):225–236. doi: 10.1016/0092-8674(95)90405-0. [DOI] [PubMed] [Google Scholar]
  29. Ikawa S., Fukui M., Ueyama Y., Tamaoki N., Yamamoto T., Toyoshima K. B-raf, a new member of the raf family, is activated by DNA rearrangement. Mol Cell Biol. 1988 Jun;8(6):2651–2654. doi: 10.1128/mcb.8.6.2651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Jansen H. W., Rückert B., Lurz R., Bister K. Two unrelated cell-derived sequences in the genome of avian leukemia and carcinoma inducing retrovirus MH2. EMBO J. 1983;2(11):1969–1975. doi: 10.1002/j.1460-2075.1983.tb01686.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kemppainen J. A., Lane M. V., Sar M., Wilson E. M. Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activation. Specificity for steroids and antihormones. J Biol Chem. 1992 Jan 15;267(2):968–974. [PubMed] [Google Scholar]
  32. Kolch W., Heidecker G., Lloyd P., Rapp U. R. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature. 1991 Jan 31;349(6308):426–428. doi: 10.1038/349426a0. [DOI] [PubMed] [Google Scholar]
  33. Kosako H., Gotoh Y., Matsuda S., Ishikawa M., Nishida E. Xenopus MAP kinase activator is a serine/threonine/tyrosine kinase activated by threonine phosphorylation. EMBO J. 1992 Aug;11(8):2903–2908. doi: 10.1002/j.1460-2075.1992.tb05359.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kyriakis J. M., App H., Zhang X. F., Banerjee P., Brautigan D. L., Rapp U. R., Avruch J. Raf-1 activates MAP kinase-kinase. Nature. 1992 Jul 30;358(6385):417–421. doi: 10.1038/358417a0. [DOI] [PubMed] [Google Scholar]
  35. Land H., Parada L. F., Weinberg R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature. 1983 Aug 18;304(5927):596–602. doi: 10.1038/304596a0. [DOI] [PubMed] [Google Scholar]
  36. Leevers S. J., Marshall C. J. Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein. EMBO J. 1992 Feb;11(2):569–574. doi: 10.1002/j.1460-2075.1992.tb05088.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Leevers S. J., Paterson H. F., Marshall C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature. 1994 Jun 2;369(6479):411–414. doi: 10.1038/369411a0. [DOI] [PubMed] [Google Scholar]
  38. Lenormand P., Sardet C., Pagès G., L'Allemain G., Brunet A., Pouysségur J. Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol. 1993 Sep;122(5):1079–1088. doi: 10.1083/jcb.122.5.1079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. Liu Y., Martindale J. L., Gorospe M., Holbrook N. J. Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway. Cancer Res. 1996 Jan 1;56(1):31–35. [PubMed] [Google Scholar]
  41. Livingstone L. R., White A., Sprouse J., Livanos E., Jacks T., Tlsty T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. doi: 10.1016/0092-8674(92)90243-6. [DOI] [PubMed] [Google Scholar]
  42. Lloyd A. C., Obermüller F., Staddon S., Barth C. F., McMahon M., Land H. Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes Dev. 1997 Mar 1;11(5):663–677. doi: 10.1101/gad.11.5.663. [DOI] [PubMed] [Google Scholar]
  43. Lowy D. R., Willumsen B. M. Function and regulation of ras. Annu Rev Biochem. 1993;62:851–891. doi: 10.1146/annurev.bi.62.070193.004223. [DOI] [PubMed] [Google Scholar]
  44. Lucibello F. C., Sewing A., Brüsselbach S., Bürger C., Müller R. Deregulation of cyclins D1 and E and suppression of cdk2 and cdk4 in senescent human fibroblasts. J Cell Sci. 1993 May;105(Pt 1):123–133. doi: 10.1242/jcs.105.1.123. [DOI] [PubMed] [Google Scholar]
  45. 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]
  46. Macleod K. F., Sherry N., Hannon G., Beach D., Tokino T., Kinzler K., Vogelstein B., Jacks T. p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes Dev. 1995 Apr 15;9(8):935–944. doi: 10.1101/gad.9.8.935. [DOI] [PubMed] [Google Scholar]
  47. Markowitz D., Hesdorffer C., Ward M., Goff S., Bank A. Retroviral gene transfer using safe and efficient packaging cell lines. Ann N Y Acad Sci. 1990;612:407–414. doi: 10.1111/j.1749-6632.1990.tb24328.x. [DOI] [PubMed] [Google Scholar]
  48. Marshall C. J. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev. 1994 Feb;4(1):82–89. doi: 10.1016/0959-437x(94)90095-7. [DOI] [PubMed] [Google Scholar]
  49. Marshall C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. doi: 10.1016/0092-8674(95)90401-8. [DOI] [PubMed] [Google Scholar]
  50. Metz T., Harris A. W., Adams J. M. Absence of p53 allows direct immortalization of hematopoietic cells by the myc and raf oncogenes. Cell. 1995 Jul 14;82(1):29–36. doi: 10.1016/0092-8674(95)90049-7. [DOI] [PubMed] [Google Scholar]
  51. Miller A. D., Rosman G. J. Improved retroviral vectors for gene transfer and expression. Biotechniques. 1989 Oct;7(9):980-2, 984-6, 989-90. [PMC free article] [PubMed] [Google Scholar]
  52. Missero C., Di Cunto F., Kiyokawa H., Koff A., Dotto G. P. The absence of p21Cip1/WAF1 alters keratinocyte growth and differentiation and promotes ras-tumor progression. Genes Dev. 1996 Dec 1;10(23):3065–3075. doi: 10.1101/gad.10.23.3065. [DOI] [PubMed] [Google Scholar]
  53. Mittnacht S., Paterson H., Olson M. F., Marshall C. J. Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein. Curr Biol. 1997 Mar 1;7(3):219–221. doi: 10.1016/s0960-9822(97)70094-0. [DOI] [PubMed] [Google Scholar]
  54. 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]
  55. Morgenstern J. P., Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990 Jun 25;18(12):3587–3596. doi: 10.1093/nar/18.12.3587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Nada S., Okada M., MacAuley A., Cooper J. A., Nakagawa H. Cloning of a complementary DNA for a protein-tyrosine kinase that specifically phosphorylates a negative regulatory site of p60c-src. Nature. 1991 May 2;351(6321):69–72. doi: 10.1038/351069a0. [DOI] [PubMed] [Google Scholar]
  57. Nakielny S., Cohen P., Wu J., Sturgill T. MAP kinase activator from insulin-stimulated skeletal muscle is a protein threonine/tyrosine kinase. EMBO J. 1992 Jun;11(6):2123–2129. doi: 10.1002/j.1460-2075.1992.tb05271.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Noda M., Ko M., Ogura A., Liu D. G., Amano T., Takano T., Ikawa Y. Sarcoma viruses carrying ras oncogenes induce differentiation-associated properties in a neuronal cell line. Nature. 1985 Nov 7;318(6041):73–75. doi: 10.1038/318073a0. [DOI] [PubMed] [Google Scholar]
  59. O'Shea C. C., Crompton T., Rosewell I. R., Hayday A. C., Owen M. J. Raf regulates positive selection. Eur J Immunol. 1996 Oct;26(10):2350–2355. doi: 10.1002/eji.1830261012. [DOI] [PubMed] [Google Scholar]
  60. Oehlen L. J., McKinney J. D., Cross F. R. Ste12 and Mcm1 regulate cell cycle-dependent transcription of FAR1. Mol Cell Biol. 1996 Jun;16(6):2830–2837. doi: 10.1128/mcb.16.6.2830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Paulus W., Baur I., Boyce F. M., Breakefield X. O., Reeves S. A. Self-contained, tetracycline-regulated retroviral vector system for gene delivery to mammalian cells. J Virol. 1996 Jan;70(1):62–67. doi: 10.1128/jvi.70.1.62-67.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Peeper D. S., Upton T. M., Ladha M. H., Neuman E., Zalvide J., Bernards R., DeCaprio J. A., Ewen M. E. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature. 1997 Mar 13;386(6621):177–181. doi: 10.1038/386177a0. [DOI] [PubMed] [Google Scholar]
  63. Peter M., Gartner A., Horecka J., Ammerer G., Herskowitz I. FAR1 links the signal transduction pathway to the cell cycle machinery in yeast. Cell. 1993 May 21;73(4):747–760. doi: 10.1016/0092-8674(93)90254-n. [DOI] [PubMed] [Google Scholar]
  64. Pritchard C. A., Samuels M. L., Bosch E., McMahon M. Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells. Mol Cell Biol. 1995 Nov;15(11):6430–6442. doi: 10.1128/mcb.15.11.6430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Pumiglia K. M., Decker S. J. Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):448–452. doi: 10.1073/pnas.94.2.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Pérez-Roger I., Solomon D. L., Sewing A., Land H. Myc activation of cyclin E/Cdk2 kinase involves induction of cyclin E gene transcription and inhibition of p27(Kip1) binding to newly formed complexes. Oncogene. 1997 May 22;14(20):2373–2381. doi: 10.1038/sj.onc.1201197. [DOI] [PubMed] [Google Scholar]
  67. 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]
  68. 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]
  69. Ridley A. J., Paterson H. F., Noble M., Land H. Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation. EMBO J. 1988 Jun;7(6):1635–1645. doi: 10.1002/j.1460-2075.1988.tb02990.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Ruley H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature. 1983 Aug 18;304(5927):602–606. doi: 10.1038/304602a0. [DOI] [PubMed] [Google Scholar]
  71. Rusch J., Levine M. Threshold responses to the dorsal regulatory gradient and the subdivision of primary tissue territories in the Drosophila embryo. Curr Opin Genet Dev. 1996 Aug;6(4):416–423. doi: 10.1016/s0959-437x(96)80062-1. [DOI] [PubMed] [Google Scholar]
  72. Samuels M. L., McMahon M. Inhibition of platelet-derived growth factor- and epidermal growth factor-mediated mitogenesis and signaling in 3T3 cells expressing delta Raf-1:ER, an estradiol-regulated form of Raf-1. Mol Cell Biol. 1994 Dec;14(12):7855–7866. doi: 10.1128/mcb.14.12.7855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Samuels M. L., Weber M. J., Bishop J. M., McMahon M. Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human raf-1 protein kinase. Mol Cell Biol. 1993 Oct;13(10):6241–6252. doi: 10.1128/mcb.13.10.6241. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Schaap D., van der Wal J., Howe L. R., Marshall C. J., van Blitterswijk W. J. A dominant-negative mutant of raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21ras. J Biol Chem. 1993 Sep 25;268(27):20232–20236. [PubMed] [Google Scholar]
  75. Serrano M., Lin A. W., McCurrach M. E., Beach D., Lowe S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997 Mar 7;88(5):593–602. doi: 10.1016/s0092-8674(00)81902-9. [DOI] [PubMed] [Google Scholar]
  76. Sewing A., Bürger C., Brüsselbach S., Schalk C., Lucibello F. C., Müller R. Human cyclin D1 encodes a labile nuclear protein whose synthesis is directly induced by growth factors and suppressed by cyclic AMP. J Cell Sci. 1993 Feb;104(Pt 2):545–555. doi: 10.1242/jcs.104.2.545. [DOI] [PubMed] [Google Scholar]
  77. Sewing A., Rönicke V., Bürger C., Funk M., Müller R. Alternative splicing of human cyclin E. J Cell Sci. 1994 Feb;107(Pt 2):581–588. doi: 10.1242/jcs.107.2.581. [DOI] [PubMed] [Google Scholar]
  78. Smith M. R., Heidecker G., Rapp U. R., Kung H. F. Induction of transformation and DNA synthesis after microinjection of raf proteins. Mol Cell Biol. 1990 Jul;10(7):3828–3833. doi: 10.1128/mcb.10.7.3828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Soddu S., Blandino G., Scardigli R., Coen S., Marchetti A., Rizzo M. G., Bossi G., Cimino L., Crescenzi M., Sacchi A. Interference with p53 protein inhibits hematopoietic and muscle differentiation. J Cell Biol. 1996 Jul;134(1):193–204. doi: 10.1083/jcb.134.1.193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Steinman R. A., Hoffman B., Iro A., Guillouf C., Liebermann D. A., el-Houseini M. E. Induction of p21 (WAF-1/CIP1) during differentiation. Oncogene. 1994 Nov;9(11):3389–3396. [PubMed] [Google Scholar]
  81. Su W. C., Kitagawa M., Xue N., Xie B., Garofalo S., Cho J., Deng C., Horton W. A., Fu X. Y. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature. 1997 Mar 20;386(6622):288–292. doi: 10.1038/386288a0. [DOI] [PubMed] [Google Scholar]
  82. Thompson T. C., Southgate J., Kitchener G., Land H. Multistage carcinogenesis induced by ras and myc oncogenes in a reconstituted organ. Cell. 1989 Mar 24;56(6):917–930. doi: 10.1016/0092-8674(89)90625-9. [DOI] [PubMed] [Google Scholar]
  83. Timchenko N. A., Wilde M., Nakanishi M., Smith J. R., Darlington G. J. CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes Dev. 1996 Apr 1;10(7):804–815. doi: 10.1101/gad.10.7.804. [DOI] [PubMed] [Google Scholar]
  84. Traverse S., Gomez N., Paterson H., Marshall C., Cohen P. Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor. Biochem J. 1992 Dec 1;288(Pt 2):351–355. doi: 10.1042/bj2880351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Traverse S., Seedorf K., Paterson H., Marshall C. J., Cohen P., Ullrich A. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr Biol. 1994 Aug 1;4(8):694–701. doi: 10.1016/s0960-9822(00)00154-8. [DOI] [PubMed] [Google Scholar]
  86. Treisman R. Regulation of transcription by MAP kinase cascades. Curr Opin Cell Biol. 1996 Apr;8(2):205–215. doi: 10.1016/s0955-0674(96)80067-6. [DOI] [PubMed] [Google Scholar]
  87. Vojtek A. B., Hollenberg S. M., Cooper J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993 Jul 16;74(1):205–214. doi: 10.1016/0092-8674(93)90307-c. [DOI] [PubMed] [Google Scholar]
  88. Warne P. H., Viciana P. R., Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993 Jul 22;364(6435):352–355. doi: 10.1038/364352a0. [DOI] [PubMed] [Google Scholar]
  89. Wassarman D. A., Therrien M., Rubin G. M. The Ras signaling pathway in Drosophila. Curr Opin Genet Dev. 1995 Feb;5(1):44–50. doi: 10.1016/s0959-437x(95)90052-7. [DOI] [PubMed] [Google Scholar]
  90. 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]
  91. Wood K. W., Qi H., D'Arcangelo G., Armstrong R. C., Roberts T. M., Halegoua S. The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5016–5020. doi: 10.1073/pnas.90.11.5016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Woods D., Parry D., Cherwinski H., Bosch E., Lees E., McMahon M. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol. 1997 Sep;17(9):5598–5611. doi: 10.1128/mcb.17.9.5598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. el-Deiry W. S., Harper J. W., O'Connor P. M., Velculescu V. E., Canman C. E., Jackman J., Pietenpol J. A., Burrell M., Hill D. E., Wang Y. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994 Mar 1;54(5):1169–1174. [PubMed] [Google Scholar]
  94. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]
  95. van Grunsven L. A., Billon N., Savatier P., Thomas A., Urdiales J. L., Rudkin B. B. Effect of nerve growth factor on the expression of cell cycle regulatory proteins in PC12 cells: dissection of the neurotrophic response from the anti-mitogenic response. Oncogene. 1996 Mar 21;12(6):1347–1356. [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES