Abstract
Mammalian cell growth is regulated by a large number of environmental cues in the form of extracellular signals. These signals stimulate changes in cell metabolism and gene expression, and induce complex cellular responses such as proliferation, differentiation, or death. However, the genetic mutations that accumulate in cancer allow cells to grow with apparent disregard for their environment, so that, even in the absence of appropriate signals, cells continue to proliferate, or they fail to differentiate or die when instructed to do so. In the past, cancer therapeutic agents were developed in the absence of a clear understanding of the mechanisms that regulate cell growth. The agents that were produced were generally developed to target rapidly dividing cells and are, on the whole, extremely toxic and associated with barely tolerable side effects, because they also target healthy dividing cells. A great deal of research has therefore been directed at understanding the molecular mechanisms that regulate cell growth and to determine why cancer cells grow with such apparent disregard for their environment. It was anticipated that this would provide new molecular targets that were associated with only the rapid division associated with cancer cells, but not with the rapid division associated with normal cells. The hope was that agents that blocked the activity of these targets would be specific for cancer cells over normal cells, leading to fewer side effects and, consequently, offering improved treatments for cancer patients.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Adachi M, Fukuda M, Nishida E. Two co-existing mechanisms for nuclear import of MAP kinases: passive diffussion as a monomer and active transport as a dimer. EMBO J 1999; 18: 5347–5358.
Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. JBiol Chem 1995; 270:27, 489–27, 494.
Badger AM, Bradbeer JN, Votta B, Lee JC, Adams JL, Griswold DE. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther 1996; 279: 1453–1461.
Behrens A, Jochum W, Sibilia M, Wagner EF. Oncogenic transformation by ras and fos is mediated by c-Jun N-terminal phosphorylation. Oncogene 2000; 19: 2657–2663.
Ben-Levy R, Hooper S, Wilson R, Paterson HF, Marshall CJ. Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. curr. Biol 1998; 8: 1049–1057.
Borsch-Haubold AG, Pasquet S, Watson SP. Direct inhibition of cyclooxigenase-1 and -2 by the kinase inhibitors SB 203580 and PD 98059. SB 203580 also inhibits thromboxane synthase. J Biol Chem 1998; 273:28, 766–28, 772.
Bos JL. Ras oncogenes in human cancer. Cancer Res 1989; 49: 4682–4689.
Bost F, McKay R, Bost M, Potapova O, Dean NM, Mercola D. The Jun kinase 2 isoform is preferentially required for epidermal growth factor-induced transformation of human A549 lung carcinoma cells. Mol Cell Biol 1999; 19: 1938–1949.
Brunet A, Rous D, Lenormand P, Dowd S, Keyse S, Pouyssegur J. Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry. EMBO J 1999; 18: 664–674.
Chao TH, Hayashi M, Tapping RI, Kato Y, Lee JD. MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. J Biol Chem 1999; 274:36, 035–36, 038.
Cheng J, Yang J, Xia Y, Karin M, Su B. Synergistic interaction of MEK kinase 2, c-Jun N-terminal kinase (JNK) kinase 2, and JNK1 results in efficient and specific JNK1 activation. Mol Cell Biol 2000; 20: 2334–2342.
Clifton AD, Young PR, Cohen P. A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress. FEBS Lett 1996; 392: 209–214.
Cohen P. The development and therapeutic potential of protein kinase inhibitors. Curr Op Chem Biol 1999; 3: 459–465.
Cowley S, Paterson H, Kemp P, Marshall CJ. Activation of MAP kinase kinase is necessary and sufficient for PC 12 differentiation and for transformation of NIH 3T3 cells. Cell 1994; 77: 841–852.
Cuenda A, Rouse J, Doza YN, Meier R, Cohen P, Gallagher TF, Young RP, Lee JC. SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1. FEBS Letters 1995; 364: 229–233.
Cunningham CC, Holmlund JT, Schiller JH, Geary RS, Kwoh TJ, Don A, Nemunaitis J. A phase I trial of c-Raf kinase antisense oligonucleotide ISIS 5132 administered as a continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res 2000; 6: 1626–1631.
Davies SP, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J 2000; 351: 95–105.
Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000; 103: 239–252.
Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 1998; 17: 4426–4441.
Denouel-Galy A, Douville EM, Warne PH, Papin C, Laugier D, Calothy G, Downward J, Eychene A. Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Curr Biol 1998; 8: 46–55.
Dickens M, Rogers JS, Cavanagh J, Raitano A, Xia Z, Halpern JR, Greenberg ME, Sawyers CL, Davis RJ. A cytoplasmic inhibitor of the JNK signal transduction pathway. Science 1998; 277: 693–696.
Druker BJ, Lydon NB. Lessons learned from the development of an Ab] tyrosine kinase inhibitor for chronic myelogenous leukemis. J Clin Invest 2000; 105: 3–7.
Dudley DT, Pang L, Decker SJ, Bridges AJ, Saltiel AR. A synthetic inhibitor of the mitogenactivated protein kinase cascade. Proc Natl Acad Sci USA 1995; 92: 7686–7689.
Eberwein D, Gianpaolo-Ostravage C, Riedl B, Lowinger T, Chien D-S, Wood J, Lyons J, Hibner B. In vivo activity of a Raf kinase inhibitor in human tumor xenograft models, p. 406. I l th NCI.EORTC.AACR Symposium on New Drugs in Caner Therapy, Amsterdam, 2000.
English JM, Vanderbilt CA, Xu S, Marcus S, Cobb MH. Isolation of MEK5 and differential expression of alternatively spliced forms. J Biol Chem 1995; 270:28, 897–28, 902.
Eyers PA, Craxton M, Morrice N, Cohen P, Goedert M. Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution. Chem Biol 1998; 5: 321–328.
Fanger GR, Gerwins P, Widmann C, Jarpe MB, Johnson GL. MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: upstream regulators of the c-Jun amino-terminal kinases? Curr Opin Genet Dev 1997; 7: 67–74.
Farrar MA, Alberol-Ila.1, Perlmutter RM. Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Nature 1996; 383: 178–181.
Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 1998; 273:18, 623–18, 632.
Fox TJ, Coll T, Xie X, Ford PJ, Germann UA, Porter MD, Pazhanisamy S, Fleming MA, Galullo V, Su MS, Wilson KP. A single amino acid substitution makes ERK2 susceptible to pyridinyl imidazole inhibitors of p38 MAP kinase. Protein Sci 1998; 7: 2249–2255.
Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J. Interleukin-I activates a novel protein kinase cascade that results in the phosphorylation of hsp27. Cell 1994; 78: 1039–1049.
Frost JA, Steen H, Shapiro P, Lewis T, Ahn N, Shaw PE, Cobb MH. Cross-cascade activation of Erks and ternary complex factors by Rho family proteins. EMBO J 1997; 16: 6426–6438.
Fukuda M, Gotoh I, Gotoh Y, Nishida E. Cytoplasmic localization of MAP kinase kinase by its N-terminal, leucine rich short amino acid sequence, which acts as a nuclear export signal. J Biol Chem 1996; 271:20, 024–20, 028.
Fukunaga R, Hunter T. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J 1997; 16: 1921–1933.
Goldman JM. Tyrosine-kinase inhibition in treatment of chronic myeloid leukaemia. The Lancet 2000; 355: 1031–1032.
Gould GW, Cuenda A, Thomson FJ, Cohen P. The activation of distinct mitogen-activated protein kinase cascades is required for the stimulation of 2-deoxyglucose uptake by interleukin-1 and insulin-like growth factor-1 in KB cells. Biochem J 1995; 311: 735–738.
Gum RJ, McLaughlin MM, Kumar S, Wang Z, Bower MJ, Lee JC, Adams JL, Livi GP, Goldsmith EJ, Young PR. Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket. J Biol Chem 1998; 273:15, 605–15, 610.
Hall-Jackson CA, Eyers PA, Cohen P, Goedert M, Boyle FT, Hewitt N, Plant H, Hedge P. Paradoxical activation of Raf by a novel Raf inhibitor. Chem Biol 1999; 6: 559–568.
Hall-Jackson CA, Goedert M, Hedge P, Cohen P. Effect of SB 203580 on the activity of c-Raf in vitro and in vivo. Oncogene 1999; 18: 2047–2054.
Hibner B, Eberwein D, Lopes T, Scialis R, Chien D-S. Pharmacokinetics of the Raf kinase inhibitor in CD-1 mice after single dose administration. 1 lth NCI.EORTC.AACR Symposium on New Drugs in Caner Therapy, Amsterdam, 2000, p. 407.
Houslay MD, Kolch W. Cell-type specific integration of cross-talk between extracellular signal-regulated kinase and cAMP signaling. Mol Pharmacol 2000; 58: 659–668.
Hu PP, Shen X, Huang D, Liu Y, Counter C, Wang XF. The MEK pathway is required for stimulation of p21(WAF1/CIPI) by transforming growth factor-beta. J Biol Chem 1999; 274:35, 381–35, 387.
Hüser M, Luckett J, Chiloeches A, Mercer K, Iwobi M, Giblett S, Sun X-M, Brown J, Marais R, Pritchard C. MEK kinase activity is not necessary for Raf-1 function. EMBO J 2001; 20 (8): 1940–1951.
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 1997; 275: 90–94.
Ip YT, Davis RJ. Signal transduction by the c-Jun N-terminal kinase (JNK)-from inflammation to development. Curr Op Cell Biol 1998; 10: 205–219.
Joneson T, Fulton JA, Volle DJ, Chaika OV, Bar-Sagi D, Lewis RE. Kinase suppressor of Ras inhibits the activation of extracellular ligand-regulated (ERK) mitogen-activated protein (MAP) kinase by growth factors, activated Ras, and Ras effectors. J Biol Chem 1998; 273: 7743–7748.
Joneson T, McDonough M, Bar-Sagi D, Van Aelst L. RAC regulation of actin polymerization and proliferation by a pathway distinct from Jun kinase [published erratum appears in Science 1997 Apr 11;276(5310):1851. Science 1996; 274: 1374–1376.
Kamakura S, Moriguchi T, Nishida E. Activation of the protein kinase ERK5/BMKI by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem 1999; 274:26, 563–26, 571.
Karandikar M, Xu S, Cobb MH. MEKK1 binds Raf-1 and the ERK2 cascade components. J Biol Chem 2000; 275:40,120–40,127.
Kato Y, Kravchenko VV, Tapping RI, Han J, Ulevitch RJ, Lee JD. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J 1997;16: 7054–7066.
Kelkar N, Gupta S, Dickens M, Davis RJ. Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3. Mol Cell Biol 2000; 20: 1030–1043.
Kolibaba KS, Druker BJ. Protein tyrosine kinase and cancer. Biochim Biophys Acta 1997; 1333: F217 - F248.
Lackey K, Cory M, Davis R, Frye SV, Harris PA, Hunter RN, Jung DK, McDonald OB, McNutt RW, Peel MR, Rutkowske RD, Veal JM, Wood ER. The discovery of potent cRaf1 kinase inhibitors. Bioorg Med Chem Lett 2000; 10: 223–226.
Lee JC, Kassis S, Kumar S, Badger A, Adams JL. p38 mitogen-activated protein kinase inhibitors-mechanisms and therapeutic potentials. Pharmacol Ther 1999; 82: 389–397.
Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, Strickler JE, McLaughlin MM, Siemens IR, Fisher SM, Livi GP, White JR, Adams JL, Young PR. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 1994; 372: 739–749.
Lewis TS, Shapiro PS, Ahn NG. Signal transduction through MAP kinase cascades. Adv Cancer Res 1998; 74: 49–139.
Liu W, Ahmad SA, Reinmuth N, Shaheen RM, Jung YD, Fan F, Ellis LM. Endothelial cell survival and apoptosis in the tumor vasculature. Apoptosis 2000; 5: 323–328.
Lloyd AC, Obermuller F, Staddon S, Barth CF, McMahon M, Land H. Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes Dev 1997; 11: 663–677.
Lowinger TB, Riedl B, Wood J, Dumas J, Smith RA, Khire U, Bankston D, Monahan MK, Scott WJ, Lee W, Johnson JS, Caringal Y, Turner T, Gane T, Kennure N, Barbosa J. Discovery of a novel class of potent Raf kinase inhibitors: structure activity relationships. 11th NCI. EORTC.AACR Symposium on New Drugs in Cancer Therapy, Amsterdam, 2000, p. 335.
Luo Z, Tzivion G, Belshaw PJ, Vavvas D, Marshall M, Avruch J. Oligomerization activates c-Raf-1 through a Ras-dependent mechanism. Nature 1996; 383: 181–185.
Mansour SJ, Matten WT, Hermann AS, Candia JM, Rong S, Fukasawa K, Vande Woude GF, Ahn NG. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 1994; 265: 966–970.
Marais R, Marshall CJ. Control of the ERK MAP kinase cascade by Ras and Raf, In: Parker PJ, Pawson T, eds. Cell Signalling, vol. 27. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1996, pp. 101–125.
Marshall C. How do small GTPase signal transduction pathways regulate cell cycle entry? Curr Biol 1999; 11: 732–736.
Marshall CJ. MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev 1994; 4: 82–89.
Marshall CJ. Ras effectors. Curr Opin Cell Biol 1996; 8: 197–204.
Marshall CJ. Specificity of receptor tyrosine kinase signalling: transient versus sustained extracellular signal-regulated kinase activation. Cell 1995; 80: 179–185.
Martin-Blanco E. p38 MAPK signaling cascades: ancient roles and new functions. Bioessays 2000; 22:637–645.
McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR. Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem 1996; 271: 8488–8492.
Milula M, Schreiber M, Husak Z, Kucerova L, Roth J, Wieser R, Zatloukal K, Beug H, Wagner E, Baccarini M. Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J,in press, 2000.
Monia BP. Anti-tumor activity of C-raf antisense-correction. Nat Med 1999; 5: 127.
Monia BP, Johnston JF, Geiger T, Muller M, Fabbro D. Antitumor activity of a phosphorothioate antisense oligodeoxynucleotide targeted against C-raf kinase. Nat Med 1996b; 2: 668–675.
Monia BP, Sasmor H, Johnston JF, Freier SM, Lesnik EA, Muller M, Geiger T, Altmann KH, Moser H, Fabbro D. Sequence-specific antitumor activity of a phosphorothioate oligodeoxyribonucleotide targeted to human C-raf kinase supports an antisense mechanism of action in vivo. Proc Natl Acad Sci USA 1996a; 93:15, 481–15, 484.
Morrison DK, Cutler REJ. The complexity of Raf-1 regulation. Curr Opin Cell Biol 1997; 9: 174–179.
Nebreda AR, Hunt T. The c-mos proto-oncogene protein kinase turns on and maintains the activity of MAP kinase, but not MPF, in cell-free extracts of Xenopus oocytes and eggs. EMBO J 1993; 12: 1979–1986.
Neckers L, Schulte TW, Mimnaugh E. Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest New Drugs 1999; 17: 361–373.
New L, Jiang Y, Zhao M, Liu K, Zhu W, Flood LJ, Kato Y, Parry GC, Han J. PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J 1998; 17: 3372–3384.
Nishio K, Fukuoka K, Fukumoto H, Sunami T, Iwamoto Y, Suzuki T, Usuda J, Saijo N. Mitogen-activated protein kinase antisense oligonucleotide inhibits the growth of human lung cancer cells. Int J Oncol 1999; 14: 461–469.
O’Dwyer Pi, Stevenson JP, Gallagher M, Cassella A, Vasilevskaya I, Monia BP, Holmlund J, Don FA, Yao KS. c-raf-1 depletion and tumor responses in patients treated with the c-raf1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A). Clin. Cancer Res 1999; 5: 3977–3982.
Okazaki K, Sagata N. MAP kinase activation is essential for oncogenic transformation of NIH3T3 cells by Mos. Oncogene 1995; 10: 1149–1157.
Pagès G, Lenormand P, L’Allemain G, Chambard JC, Meloche S, Pouysségur J. Mitogenactivated protein kinase p42maPk and p44maPk are required for fibroblast proliferation. Proc Natl Acad Sci USA 1993; 90 (18): 8319–8323.
Pierrat B, Correia JS, Mary JL, Tomas-Zuber M, Lesslauer W. RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogenactivated protein kinase (p38alphaMAPK). J Biol Chem 1998; 273:29, 661–29, 671.
Posada J, Yew N, Ahn NG, Vande Woude GF, Cooper JA. Mos stimulates MAP kinase in Xenopus oocytes and activates a MAP kinase kinase in vitro. Mol Cell Biol 1993; 13: 2546–2553.
Potapova O, Gorospe M, Bost F, Dean NM, Gaarde WA, Mercola D, Holbrook NJ. c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells. J Biol Chem 2000b; 275:24, 757–24, 775.
Potapova O, Gorospe M, Dougherty RH, Dean NM, Gaarde WA, Holbrook NJ. Inhibition of c-Jun N-terminal kinase 2 expression suppresses growth and induces apoptosis of human tumor cells in a p53-dependent manner. Mol Cell Biol 2000a; 20: 1713–1722.
Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR. Phosphorylation of c-jun mediated by MAP kinases. Nature 1991; 353: 670–674.
Pumiglia KM, Decker SJ. Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 1997; 94: 448–452.
Reuter CWM, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malingnancies? Blood 2000; 96: 1655–1669.
Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 1997; 9: 180–186.
Roovers K, Assoian RK. Integrating the MAP kinase signal into the Gl phase cell cycle machienary. BioEssays 2000; 22: 818–826.
Schaeffer HJ, Catling AD, Eblen ST, Collier LS, Krauss A, Weber MJ. MP 1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 1998; 281: 1668–1671.
Schlesinger TK, Fanger GR, Yujiri T, Johnson GL. The TAO of MEK. Front Biosci 1998; 15: D1181 - D1186.
Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000; 103: 211–225.
Sebolt-Leopold JS, Dudley DT, Herrera R, Van Becelaere K, Wiland A, Gowan RC, Tecle H, Barrett SD, Bridges A, Przybranowski S, Leopold WR, Saltiel AR. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat Med 1999; 5: 810–816.
Sewing A, Wiseman B, Lloyd AC, Land H. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol 1997; 17: 5588–5597.
Sithanandam G, Latif F, Duh FM, Bernal R, Smola U, Li H, Kuzmin I, Wixler V, Geil L, Shrestha S, Lloyd PA, Bader I, Sekido Y, Tartof K, Kashuba VI, Zabarovsky ER, Dean M, Klein G, Lerman MI, Minna JD, Rapp UR, Allikmets R. 3pK, a new mitogen-activated protein kinase-activated protein kinase located in the small cell lung cancer tumor suppressor gene region. Mol Cell Biol 1996; 16: 868–876.
Smeal T, Binétruy B, Mercola DA, Birrer M, Karin M. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature 1991; 354: 494–496.
Stevenson JP, Yao KS, Gallagher M, Friedland D, Mitchell EP, Cassella A, Monia B, Kwoh TJ, Yu R, Holmlund J, Dorr FA, O’Dwyer PJ. Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A). J Clin Oncol 1999; 17: 2227–2236.
Stokoe D, Campbell DG, Nakielny S, Hidaka H, Leevers SJ, Marshall CJ, Cohen P. MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase. EMBO J 1992; 11: 3985–3994.
Stokoe D, Engel K, Campbell DG, Cohen P, Gaestel M. Identification of MAPKAP kinase 2 as a major enzyme responsible for the phosphorylation of the small mammalian heat shock proteins. FEBS Letters 1992; 313: 307–313.
Sturgill TW, Ray LB, Erikson E, Mailer JL. Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature 1988; 334: 715–718.
Su GH, Hilgers W, Shekher MC, Tang DJ, Yeo Ci, Hruban RH, Kern SE. Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res 1998; 58: 2339–2342.
Sun W, Kesavan K, Schaefer BC, Garrington TP, Ware M, Johnson NL, Gelfand EW, Johnson GL. MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5BMK1/ERK5 pathway. J Biol Chem 2000; 276: 5093–5100.
Tan Y, Rouse J, Zhang A, Cariati S, Cohen P, Comb MJ. FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J 1996; 15: 4629–4642.
Teng DH, Perry WL, Hogan JK, Baumgard M, Bell R, Berry S, Davis T, Frank D, Frye C, Hattier T, Hu R, Jammulapati S, Janecki T, Leavitt A, Mitchell JT, Pero R, Sexton D, Schroeder M, Su PH, Swedlund B, Kyriakis JM, Avruch J, Bartel P, Wong AK, Tavtigian S V, et al. Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. Cancer Res 1997; 57: 4177–4182.
Therrien M, Michaud NR, Rubin GM, Morrison DK. KSR modulates signal propagation within the MAPK cascade. Genes and Dey 1996; 10: 2684–2695.
Treisman R. Regulation of transcription by MAP kinase cascades. Curr Op Cell Biol 1996; 8: 205–215.
Vojtek AB, Der C.T. Increasing complexity of the Ras signaling pathway. J Biol Chem 1998; 273:19, 925–19, 928.
Waskiewicz AJ, Flynn A, Proud CG, Cooper JA. Mitogen-activated protein kinases activate the serine/threonine kinases Mnkl and Mnk2. EMBO J 1997; 16: 1909–1920.
Whitmarsh Ai, Cavanagh J, Tournier C, Yasuda J, Davis RJ. A mammalian scaffold complex that selectively mediates MAP kinase activation. Science 1998; 281: 1671–1674.
Whitmarsh AJ, Davis RJ. Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. Trends Biochem Sci 1998; 23: 481–485.
Wilhelm S, Kennure N, Housley T, Katz M, Wood J, Lyons J, Taylor R, Knepper M, Roscoe W, Bollag G. A novel Raf kinase inhibitor blocks the Raf/MEK/ERk pathway in tumor cells. 11th NCI.EORTC.AACR Symposium on New Drugs in Caner Therapy, Amsterdam, 2000, p. 405.
Wilson KP, McCaffrey PG, Hsiao K, Pazhanisamy S, Galullo V, Bemis GW, Fitzgibbon MJ, Caron PR, Murcko MA, Su MS. The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase. Chem Biol 1997; 4: 423–431.
Winston BW, Chan ED, Johnson GL, Riches DW. Activation of p38mapk, MKK3, and MKK4 by TNF-alpha in mouse bone marrow-derived macrophages. J Immunol 1997; 159: 4491–4497.
Wittinghofer A, Waldmann H. Ras-a molecular switch involved in tumour formation. Angew Chem Int Ed 2000; 39: 4192–4214.
Wojnowski L, Stancato LF, Zimmer AM, Hahn H, Beck TW, Lamer AC, Rapp UR, Zimmer A. Craf- 1 protein kinase is essential for mouse development. Mech Dey 1998; 76: 141–149.
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 p21 Cip 1. Mol Cell Biol 1997; 17: 5598–5611.
Xia Y, Wu Z, Su B, Murray B, Karin M. JNKK1 organises a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino terminal extension. Gene Dey 1998; 12: 3369–3381.
Xing H, Kornfeld K, Muslin A. The protein kinase KSR interacts with 14–3–3 protein and Raf. Curr Biol 1997; 7: 294 – 300.
Yasuda J, Whitmarsh AJ, Cavanagh J, Sharma M, Davis RJ. The JIP group of mitogenactivated protein kinase scaffold proteins. Mol Cell Biol 1999; 19: 7245–7254.
Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, Kolch W. Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol Cell Biol 2000; 20: 3079–3085.
Yeung K, Seitz T, Li S, Janosch P, McFerran B, Kaiser C, Fee F, Katsanakis KD, Rose DW, Mischak H, Sedivy JM, Kolch W. Suppression of Raf-1 kinase activity and MAP kinase signaling by RKIP. Nature 1999; 401: 173–177.
Yoshida BA, Dubauskas, Chekmareva MA, Christiano TR, Stadler WM, Rinker-Schaeffer CW. Mitogen-activated protein kinase kinase 4/stress-activated protein/Erk kinase 1 (MKK4/ SEK1), a prostate cancer metastasis suppressor gene encoded by human chromosome 17. Cancer Res 1999; 59: 5483–5487.
Young PR, McLaughlin MM, Kumar S, Kassis S, Doyle ML, McNulty D, Gallagher TF, Fisher S, McDonnell PC, Can SA, Huddleston MJ, Seibel G, Porter TG, Livi GP, Adams JL, Lee JC. Pyridinyl imidazole inhibitors of p38 mitogen-activated protein kinase bind in the ATP site. JBiol Chem 1997; 272:12, 116–12, 121.
Zhao Y, Bjorbaek C, Weremowicz S, Morton CC, Moller DE. RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation. Mol Cell Biol 1995; 15: 4353–4363.
Zhou G, Bao ZQ, Dixon JE. Components of a new human protein kinase signal transduction pathway. J Biol Chem 1995; 270:12, 665–12, 669.
Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes and Dev 1998; 12: 2997–3007.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer Science+Business Media New York
About this chapter
Cite this chapter
Chiloeches, A., Marais, R. (2002). Mitogen-Activated Protein Kinase Cascades as Therapeutic Targets in Cancer. In: La Thangue, N.B., Bandara, L.R. (eds) Targets for Cancer Chemotherapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-153-4_9
Download citation
DOI: https://doi.org/10.1007/978-1-59259-153-4_9
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-61737-263-6
Online ISBN: 978-1-59259-153-4
eBook Packages: Springer Book Archive