Hostname: page-component-586b7cd67f-tf8b9 Total loading time: 0 Render date: 2024-11-25T18:42:25.293Z Has data issue: false hasContentIssue false
  • English
  • Français

Neurotrophin Regulation of Gene Expression

Published online by Cambridge University Press:  18 September 2015

Azad Bonni  and
Michael E. Greenberg
Azad Bonni*
Affiliation:
Division of Neuroscience, Children's Hospital, and the Department of Neurobiology, Harvard Medical School, Boston
Michael E. Greenberg
Affiliation:
Division of Neuroscience, Children's Hospital, and the Department of Neurobiology, Harvard Medical School, Boston
*
Division of Neuroscience, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115 U.S.A.
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The neurotrophins comprise a family of secreted proteins that elicit profound responses in cells of the developing and mature vertebrate nervous system including the regulation of neuronal survival and differentiation. The molecular mechanisms by which the neurotrophins exert their effects have been the subject of intense investigation. The neurotrophins elicit responses in neurons via members of the Trk family of receptors and the p75 neurotrophin receptor. Once activated, neurotrophin receptors trigger a large number of biochemical events that propagate the neurotrophin signal from the plasma membrane to the interior of the cell. An important target of the neurotrophin-induced signaling pathways is the nucleus, where neurotrophin-induced signals are coupled to alterations in gene expression. These neurotrophin-induced changes in gene expression are critical for many of. the phenotypic effects of neurotrophins including the regulation of neuronal survival and differentiation.

Type
Review Articles
Information
Canadian Journal of Neurological Sciences , Volume 24 , Issue 4 , November 1997 , pp. 272 - 283
Copyright
Copyright © Canadian Neurological Sciences Federation 1997

References

REFERENCES

1.Levi-Montalcini, R. The nerve growth factor 35 years later. Science 1987; 237: 1154–1162.CrossRefGoogle ScholarPubMed
2.Jelsma, TN, Aguayo, AJ. Trophic factors. Curr Opin Neurobiol 1994; 4: 717–725.CrossRefGoogle ScholarPubMed
3.Yuen, EC, Mobley, WC. Therapeutic potential of neurotrophic factors for neurological disorders. Ann Neurol 1996; 40: 346–354.CrossRefGoogle ScholarPubMed
4.Ip, NY, Yancopoulos, GD. The neurotrophins and CNTF: two families of collaborative neurotrophic factors. Ann Rev Neurosci 1996; 19: 491–515.CrossRefGoogle ScholarPubMed
5.Lewin, GR, Barde, Y-A. Physiology of the neurotrophins. Ann Rev Neurosci 1996; 19: 289–317.CrossRefGoogle ScholarPubMed
6.Snider, WD. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 1994; 77: 627–638.CrossRefGoogle ScholarPubMed
7.Kalcheim, C, Carmeli, C, Rosenthal, A. Neurotrophin 3 is a mitogen for cultured neural crest cells. Proc Natl Acad USA 1992; 89: 1661–1665.CrossRefGoogle ScholarPubMed
8.Dicicco-Bloom, E, Friedman, WJ, Black, IB. NT-3 stimulates sympathetic neuroblast proliferation by promoting precursor survival. Neuron 1993; 11: 1101–1111.CrossRefGoogle ScholarPubMed
9.Levi-Montalcinin, R, Booker, B. Destruction of the sympathetic ganglia in mammals by an antiserum to a nerve growth factor protein. Proc Natl Acad Sci USA 1960; 46: 384–391.CrossRefGoogle Scholar
10.Crowley, C, Spencer, SD, Nishimura, MCet al. Mice lacking nerve growth factor display perinatal loss of sensory and sympathetic neurons yet develop basal forebrain cholinergic neurons. Cell 1994; 76: 1001–1012.CrossRefGoogle ScholarPubMed
11.Smeyne, RJ, Klein, R, Schnapp, Aet al. Severe sensory and sympathetic neuropathies in mice carrying a disrupted trk/NGF receptor gene. Nature 1994; 368: 246–249.CrossRefGoogle Scholar
12.Hory-Lee, F, Russell, M, Lindsay, RMFrank, E. Neurotrophin 3 supports the survival of developing muscle sensory neurons in culture. Proc Natl Acad Sci USA 1993; 90: 2613–2617.CrossRefGoogle ScholarPubMed
13.Ernfors, P, Lee, K-F, Kucera, J, Jaenisch, R. Lack of neurotropin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell 1994; 77: 503–512.CrossRefGoogle Scholar
14.Klein, R, Silos-Santiago, I, Smeyne, RJ, et al. Disruption of the neurotrophin-3 receptor gene trkC eliminates Ia muscle afferents and results in abnormal movements. Nature 1994; 368: 249–251.CrossRefGoogle ScholarPubMed
15.Jones, KR, Farinas, I, Backus, C, Reichardt, LF. Targeted disruption of the brain-derived neurotrophic factor gene perturbs brain and sensory neuron but not motor neuron development. Cell 1994; 76: 989–1000.CrossRefGoogle Scholar
16.Hefti, F. Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 1986; 6: 2155–2162.CrossRefGoogle ScholarPubMed
17.Fischer, W, Wictorin, K, Bjorklund, A. Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 1987; 326: 65–68.CrossRefGoogle Scholar
18.Ghosh, A, Greenberg, ME. Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis. Neuron 1995; 15: 1–20.CrossRefGoogle ScholarPubMed
19.Vicario-Abejon, C, Johe, KK, Hazel, TG, Collazo, D, McKay, RDG. Functions of basic fibroblast growth factor and neurotrophins in the differentiation of hippocampal neurons. Neuron 1995; 15: 105–114.CrossRefGoogle ScholarPubMed
20.Sendtner, M, Holtmann, B, Kolbeck, R, Thoenen, H, Barde, Y-A. Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. Nature 1992; 360: 757–759.CrossRefGoogle ScholarPubMed
21.Yan, Q, Elliot, J, Snider, WD. Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 1992; 360: 753–755.CrossRefGoogle ScholarPubMed
22.Henderson, CE, Camu, W, Mettling, C, et al. Neurotrophins promote motor neuron survival and are present in embryonic limb bud. Nature 1993; 363: 266–270.CrossRefGoogle ScholarPubMed
23.Sutter, A, Riopelle, RJ, Harris-Warrick, RM, Shooter, EM. Nerve growth factor receptors. Characterization of two distinct classes of binding sites on chick embryo sensory ganglia cells. J Biol Chem 1978; 82: 5972–5982.Google Scholar
24.Chao, MV, Bothwell, MA, Ross, AH, et al. Gene transfer and molecular cloning of the human NGF receptor. Science 1986; 232: 518–521.CrossRefGoogle ScholarPubMed
25.Johnson, D, Lanahan, A, Buck, CR, et al. Expression and structure of the human NGF receptor. Cell 1986; 47: 545–554.CrossRefGoogle ScholarPubMed
26.Radeke, MJ, Misko, TP, Hsu, C, Herzenberg, LA, Shooter, EM. Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature 1987; 325: 593–597.CrossRefGoogle ScholarPubMed
27.Chao, MV. Neurotrophin receptors: a window into neuronal differentiation. Neuron 1992b; 9: 583–593.CrossRefGoogle ScholarPubMed
28.Bothwell, M. Functional interactions of neurotrophins and neurotrophin receptors. Ann Rev Neurosci 1995; 18: 223–253.CrossRefGoogle ScholarPubMed
29.Kaplan, DR, Hempstead, B, Martin-Zanca, D, Chao, MV, Parada, LF. The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 1991a; 242: 554–558.CrossRefGoogle Scholar
30.Kaplan, D, Martin-Zanca, D, Parada, LF. Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 1991b; 350: 158–160.CrossRefGoogle ScholarPubMed
31.Klein, R, Jing, S, Nanduri, V, O’Rourke, E, Barbacid, M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 1991; 65: 189–197.CrossRefGoogle ScholarPubMed
32.Greene, LA, Tischler, AS. PC12 pheochromocytoma cultures in neurobiological research. Adv Cell Neurobiol 1982; 3: 373–414.CrossRefGoogle Scholar
33.Halegoua, S, Armstrong, RC, Kremer, NE. Dissecting the mode of action of a neuronal growth factor. Curr Top Microb Immun 1990; 165: 119–170.Google Scholar
34.Loeb, D, Maragos, J, Martin-Azanca, D, Chao, MV, Greene, LA. The trk proto-oncogene rescues NGF responsiveness in mutant NGF-nonresponsive PC12 cell lines. Cell 1991; 66: 961–966.CrossRefGoogle ScholarPubMed
35.Hempstead, BL, Rabin, SJ, Kaplan, L, et al. Overexpression of the trk tyrosine kinase rapidly accelerates nerve growth factorinduced differentiation. Neuron 1992; 9: 883–896.CrossRefGoogle ScholarPubMed
36.McDonald, NQ, Lapatto, R, Murray-Rust, J, et al. New protein fold revealed by a 2.3 A resolution crystal structure of nerve growth factor. Nature 1991; 354: 411–414.CrossRefGoogle ScholarPubMed
37.Heldin, C. Dimerization of cell surface receptors in signal transduction. Cell 1995; 1995: 213–223.CrossRefGoogle Scholar
38.Koch, CA, Anderson, D, Moran, MF, Ellis, C, Pawson, T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science 1991; 252: 668–674.CrossRefGoogle ScholarPubMed
39.Cohen, GB, Ren, R, Baltimore, D. Modular binding domains in signal transduction proteins. Cell 1995; 80: 237–248.CrossRefGoogle ScholarPubMed
40.van der Geer, P, Pawson, T. The PTB domain: a new protein module implicated in signal transduction. Trends Biochem Sci 1995; 20: 277–280.CrossRefGoogle ScholarPubMed
41.Songyang, Z, Shoelson, SE, Chaudhuri, M, et al. SH2 domains recognize specific phosphopetide sequences. Cell 1993; 72: 767–778.Google Scholar
42.Obermeier, A, Halfter, H, Wiesmuller, KH, et al. Tyrosine 785 is a major determinant of Trk-substrate interaction. EMBO J 1993a; 12: 933–941.CrossRefGoogle Scholar
43.Obermeier, A, Lammers, R, Wiesmuller, K, et al. Identification of trk binding sites for SHC and phosphatidylinositol 3’-kinase and formation of a multimeric signaling complex. J Biol Chem 1993b; 268: 22963–22966.CrossRefGoogle ScholarPubMed
44.Bar-Sagi, D, Feramisco, JR. Microinjection of the ras oncogene protein into PC12 cells induces morphologic differentiation. Cell 1985; 42: 841–848.CrossRefGoogle Scholar
45.Hagag, N, Halegoua, S, Viola, M. Inhibition of growth factorinduced differentiation of PC 12 cells by microinjection of antibody to ras p21. Cell 1986; 319: 680–682.Google Scholar
46.Stephens, RD, Loeb, D, Copeland, T, et al. Trk receptors use redundant signal transduction pathways involving SHC and PLC gamma 1 to mediate NGF responses. Neuron 1994; 12: 691–705.CrossRefGoogle ScholarPubMed
47.Rozakis-Adcock, M, McGlade, J, Mbamulu, G, et al. Association of the She and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature 1992; 360: 689–692.CrossRefGoogle Scholar
48.Lowenstein, E, Daly, R, Batzer, A, et al. The SH2 and SH3 domaincontaining protein GRB2 links receptor tyrosine kinases to ras signalling. Cell 1992; 70: 431–442.CrossRefGoogle Scholar
49.McCormick, F, Activators and effectors of ras p21 proteins. Curr Opin Genet Devel 1994; 4: 71–76.CrossRefGoogle ScholarPubMed
50.Thomas, SM, DeMarco, M, D’Arcangelo, G, Holegoua, S, Brugge, J. Ras is essential for nerve growth factor and phorbol ester induced tyrosine phosphorylation of MAP kinases. Cell 1992; 68: 1031–1040.CrossRefGoogle ScholarPubMed
51.Wood, KW, Sarnecki, C, Roberts, TM, Blenis, J. Ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell 1992; 68: 1041–1050.CrossRefGoogle ScholarPubMed
52.Leevers, SJ, Paterson, HF, Marshall, CJ. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 1994; 364: 411–414.CrossRefGoogle Scholar
53.Marais, R, Light, Y, Paterson, HF, Marshall, CJ. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phopshorylation. EMBO J 1995; 14: 3136–3145.CrossRefGoogle Scholar
54.Alessi, DR, Saito, Y, Campbell, DG, et al. Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-l. EMBO J 1994; 13: 1610–1619.CrossRefGoogle Scholar
55.Cowley, S, Paterson, H, Kemp, P, Marshall, CJ. Activation of MAP kinase kinase is necessary and sufficient for PC12 cell differentiation and for transformation of N1H 3T3 cells. Cell 1994; 77: 841–852.CrossRefGoogle Scholar
56.Marshall, CJ. MAP kinase kinase kinase, MAP kinase kinase, and MAP kinase. Curr Opin Genet Devel 1994; 4: 82–89.CrossRefGoogle ScholarPubMed
57.Blenis, J. Signal transduction via the MAP kinases: proceed at your own rsk. Proc Natl Acad Sci. 1993; 90: 5889–5892.CrossRefGoogle ScholarPubMed
58.Marshall, CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995; 80(2): 179–185.CrossRefGoogle ScholarPubMed
59.Chen, RH, Sarnecki, C, Blenis, J. Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol. 1992; 12: 915–927.Google ScholarPubMed
60.Greene, LA, Burstein, DE, Black, MM. The role of transcriptiondependent priming in nerve growth factor promoted neurite outgrowth. Dev Biol. 1982; 91: 305–316.CrossRefGoogle ScholarPubMed
61.Chao, MV. Growth factor signaling: where is the specificity? Cell 1992a; 68: 995–997.CrossRefGoogle ScholarPubMed
62.Greenberg, ME, Greene, LA, Ziff, EB. Nerve growth factor and epidermal growth factor induce rapid transient changes in protooncogene transcription in PC12 cells. J Biol Chem 1985; 260: 14101–14110.CrossRefGoogle ScholarPubMed
63.Sheng, M, Greenberg, ME. The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron 1990; 4: 477–485.CrossRefGoogle ScholarPubMed
64.Herschman, H. Primary response genes induced by growth factor and tumor promoters. Annu Rev Biochem 1991; 60: 281–319.CrossRefGoogle Scholar
65.Curran, T, Franza, BRJ. Fos and Jun: the AP-1 connection. Cell 1988; 55: 395–397.CrossRefGoogle ScholarPubMed
66.Johnson, RS, Spiegelman, BM, Papaioannou, VE. Pleitropic effects of a null mutation in the c-fos proto-oncogene. Cell 1992; 74: 577–586.CrossRefGoogle Scholar
67.Morgan, JI, Curran, T. Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Ann Rev Neurosci 1991; 14: 421–451.CrossRefGoogle ScholarPubMed
68.Greenberg, ME, Hermanowski, AL, Ziff, EB. Effect of protein synthesis inhibitors on growth factor activation of c-fos, c-myc, and actin gene transcription. Mol Cell Biol 1986; 6: 1050–1057.Google ScholarPubMed
69.Treisman, R. Transient accumulation of c-fos RNA following serum stimulation requires a conserved 5’ element and c-fos 3’ sequences. Cell 1985; 42: 567–574.CrossRefGoogle ScholarPubMed
70.Hayes, TE, Kitchen, AM, Cochran, BH. Inducible binding of a factor to the c-fos regulatory region. Proc Natl Acad Sci USA 1987; 84: 1272–1276.CrossRefGoogle Scholar
71.Sheng, M, Dougan, ST, McFadden, G, Greenberg, ME. Calcium and growth factor pathways of c-fos transcriptional activation require distinct upstream regulatory sequences. Mol Cell Biol 1988; 8: 2787–2796.Google ScholarPubMed
72.Sassone-Corsi, P, Visvader, J, Ferland, L, Mellon, P, Verma, IM. Induction of proto-oncogene fos transcription through the adenylate cyclase pathway: characterization of a cAMP-response element. Genes Dev 1988; 2: 1529–1538.CrossRefGoogle Scholar
73.Fisch, TM, Prywes, R, Roeder, RG. c-fos sequences necessary for basal expression and induction by epidermal growth factor, 12-O-tetradecanoyl phorbol-13-acetate, and the calcium ionophore. Mol Cell Biol 1987; 7: 3490–3496.Google ScholarPubMed
74.Berkowitz, LA, Riabowal, KT, Gilman, MZ. Multiple sequence elements of a single functional class are required for cyclic AMP responsiveness of the mouse c-fos promoter. Mol Cell Biol 1989; 9: 4272–4281.Google ScholarPubMed
75.Treisman, R. The serum response element. Trends Bioch Sci 1992; 17: 423–426.CrossRefGoogle ScholarPubMed
76.Treisman, R. Identification of a protein binding site that mediates transcriptional response of the cfos gene to serum factors. Cell 1986; 46: 567–574.CrossRefGoogle ScholarPubMed
77.Gilman, MZ, Wilson, RN, Weinberg, RA. Multiple protein binding sites in the 5’-flanking region regulate cfos expression. Mol Cell Biol 1986; 6: 4305–4315.Google Scholar
78.Greenberg, ME, Siegfried, Z, Ziff, EB. Mutation of the c-fos gene dyad symmetry element inhibits serum inducibility of transcription in vivo and the nuclear regulatory factor binding in vitro. Mol Cell Biol 1987; 7: 1217–1225.Google ScholarPubMed
79.Rivera, VM, Sheng, M, Greenberg, ME. The inner core of the serum response element mediates both the rapid induction and subsequent repression of c-fos transcription following serum stimulation. Genes Dev 1990; 4: 255–268.CrossRefGoogle ScholarPubMed
80.Bonni, A, Ginty, DD, Dudek, H, Greenberg, ME. Serine 133-phosphorylated CREB induces transcription via a cooperative mechanism that may confer specificity to neurotrophin signals. Cell Neurosci 1995; 6(2): 168–183.CrossRefGoogle Scholar
81.Rivera, VM, Miranti, CK, Misra, RP, et al. A growth factor-induced kinase phosphorylates the serum response factor at a site that regulates its DNA-binding activity. Mol Cell Biol 1993; 13: 6260–6273.Google Scholar
82.Miranti, CK, Ginty, DD, Huang, G, Chatila, T, Greenberg, ME. Calcium activates serum response factor-dependent transcription by a Ras- and Elk-1-independent mechanism that involves a Ca2+/calmodulin-dependent kinase. Mol Cell Biol 1995; 15(7): 3672–3684.CrossRefGoogle ScholarPubMed
83.Dalton, S, Treisman, R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell 1992; 68: 597–612.CrossRefGoogle Scholar
84.Hipskind, RA, Rao, VN, Mueller, CGReddy, ESP, Nordheim, A. Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Nature 1991; 354: 531–534.CrossRefGoogle Scholar
85.Gille, R, Sharrocks, AD, Shaw, PE. Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at the c-fos promoter. Nature 1992; 358: 414–417.CrossRefGoogle ScholarPubMed
86.Marais, R, Wynne, J, Treisman, R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 1993; 73: 381–393.CrossRefGoogle ScholarPubMed
87.Zinck, R, Hipskind, RA, Pingoud, V, Nordheim, A. c-fos transcriptional activation and repression correlate temporally with the phosphorylation status of TCF. EMBO J 1993; 12: 2377–2387.CrossRefGoogle ScholarPubMed
88.Ryan, WA, Franza, BR Jr., Gilman, MZ. Two distinct cellular phosphoproteins bind to the c-fos serum element. EMBO J 1989; 8: 1785–1792.CrossRefGoogle Scholar
89.Walsh, K. Cross-binding of factors to functionally different promoter elements in c-fos and skeletal actin genes. Mol Cell Biol 1989; 9: 2191–2201.Google ScholarPubMed
90Natesan, S, Gilman, MZ. DNA bending and orientation-dependent function of YY1 in the c-fos promoter. Genes Dev 1993; 7: 2497–2509.CrossRefGoogle ScholarPubMed
91Gualberto, AD, Lepage, G, Pons, SL, et al. Functional antagonism between YYI and the serum response factor. Mol Cell Biol 1992; 12: 4209–4214.Google Scholar
92Natesan, S, Gilman, M. YYI facilitates the association of serum response factor with the c-fos serum response element. Mol Cell Biol 1995; 15 (11): 5975–5982.CrossRefGoogle Scholar
93Gruenberg, DA, Natesan, S, Alexandre, C, Gilman, MZ. Human and Drosophila homeodomain proteins that enhance the DNA-binding activity of serum response factor. Science 1992; 257: 1089–1094.CrossRefGoogle Scholar
94Ginty, DD, Bonni, A, Greenberg, ME, NGF activates a Ras-dependent protein kinase that stimulates c-fos transcription via phosphorylation of CREB. Cell 1994; 77: 713–725.CrossRefGoogle ScholarPubMed
95Fisch, TM, Prywes, R, Simon, MC, Roeder, RG. Multiple sequence elements in the c-fos promoter mediateinduction by cAMP. Genes Dev 1989; 3: 198–211.CrossRefGoogle ScholarPubMed
96Brindle, PK, Montminy, MR, The CREB family of transcription factors. Cur Opin Gen Dev 1992; 2: 199–204.CrossRefGoogle Scholar
97Meyer, TK, Habener, JF, Cyclic adenosine 3’,5’-monophosphate response element binding protein (CREB) and related transcription- activating deoxyribonucleic acid-binding proteins. Endocrine Rev 1993; 14: 269–290.Google ScholarPubMed
98Sheng, ME, Thompson, MA, Greenberg, MECREB: a Ca+2-regulated transcription factor phosphorylated by CaM kinases. Science 1991; 252: 1427–1430.CrossRefGoogle Scholar
99Gonzalez, GA, Montminy, MR. Cyclic AMP stimulates somatostatingene transcription by phosphorylationof CREB at Serine 133. Cell 1989; 59: 675–680.CrossRefGoogle Scholar
100Xing, J, Ginty, DD, Greenberg, ME. Coupling of the Ras-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 1996; 273: 959–963.CrossRefGoogle ScholarPubMed
101Chrivia, JC, Kwok, RPS, Lamb, N, et al. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 1993; 365: 855–859.CrossRefGoogle Scholar
102Kwok, RPS, Lundblad, JR, Chrivia, JC, et al. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 1994; 370: 223–223.CrossRefGoogle ScholarPubMed
103Traverse, S, Seedorf, K, Paterson, H, et al. EGF triggers neuronal differentiation of PC 12 cells that overexpress the EGF receptor. CurrBiol 1994; 4: 694–701.Google Scholar
104Hu, Q, Klippel, A, Muslin, AJ, Fantl, WJ,Williams, LT. Ras-dependent induction of cellular responsesby constitutively active phosphatidylinositol-3 kinase. Science 1995; 268: 100–102.CrossRefGoogle Scholar
105Yao, R, Cooper, GM. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 1995; 267: 2003–2006.CrossRefGoogle ScholarPubMed
106Divecha, N, Irvine, RF. Phospholipid signaling. Cell 1995; 80: 269–278.CrossRefGoogle ScholarPubMed
107Franke, TK, Kaplan, DR, Cantley, LC. PI3K: downstream AKTion blocks apoptosis. Cell 1997; 88: 435–437.CrossRefGoogle ScholarPubMed
108Burgering, B, Coffer, P. Protein kinase B (Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 1995; 376: 599–602.CrossRefGoogle ScholarPubMed
109Franke, TF, Yang, SIChan, TO, et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 1995; 81: 727–736.CrossRefGoogle ScholarPubMed
110Dudek, H, Datta, SR, Franke, TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275: 661–665.CrossRefGoogle ScholarPubMed
111Chung, J, Grammer, T, Lemmon, K,Kazlauskas, A, Blenis, J. PDGF and insulin-dependent pp70S6K activation mediated byphosphatidylinositol- 3-OH kinase. Nature 1994; 370: 71–75.CrossRefGoogle Scholar
112de Groot, RP, Ballou, LM, Sassone-Corsi, P. Positive regulation of the cAMP-responsive activator CREM by the p70 S6 kinase: an alternative route to mitogen-induced gene expression. Cell 1994; 79: 81–91.CrossRefGoogle ScholarPubMed
113Rabin, S, Cleghorn, V, Kaplan, DR. SNT, a differentiation-specific target of neurotrophic factor-induced tyrosine kinase activity in neurons and PC12 cells. Mol Cell Biol 1993; 13: 2203–2213.Google ScholarPubMed
114Peng, X, Greene, L, Kaplan, DR, Stephens, R.Deletion of a conserved juxtamembrane sequence in Trk abolishes NGF-promoted neuritogenesis. Neuron 1995; 15: 395–406.CrossRefGoogle ScholarPubMed
115Hill, CS, Treisman, R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell 1995; 80: 199–211.CrossRefGoogle ScholarPubMed
116Gupta, S, Campbell, D, Derijard, B, Davis, RJ. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 1995; 267: 389–393.CrossRefGoogle ScholarPubMed
117Whitmarsh, AJ, Shore, P, Sharrocks, AD, Davis, RJ. Integration of MAP kinase signal transduction pathways at the serum response element. Science 1995; 269: 403–407.CrossRefGoogle ScholarPubMed
118Vojtek, A, Cooper, JA. Rho family members: activators of MAP kinase cascades. Cell 1995; 82: 527–529.CrossRefGoogle ScholarPubMed
119Xia, Z, Dickens, M, Raingeaud, J, Davis, RJ, Greenberg, ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 1995; 270: 1326–1334.CrossRefGoogle ScholarPubMed
120Verheij, M, Bose, R, Lin, XH, et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 1996; 380: 75–79.CrossRefGoogle ScholarPubMed
121Joseph, C, Byun, H, Bittman, R, Kolesnick, R. Substrate recognition by ceramide-activated protein kinase. J Biol Chem 1994; 268: 20002–20006.CrossRefGoogle Scholar
122Yao, B, Zhang, Y, Delikat, S, et al. Phosphorylation of Raf by ceramide-activated protein kinase. Nature 1995; 378: 307–310.CrossRefGoogle ScholarPubMed
123Dobrowsky, RT, Werner, MH, Castellino, AM, Chao, MV, Hannun, YA. Activation of the sphingomyelinase cycle through the lowaffinity neurotrophin receptor. Science 1994; 265: 1596–1599.CrossRefGoogle Scholar
124Barker, PA, Shooter, EP. Disruption of NGF binding to the low affinity neurotrophin receptor p75-LNTR reduces NGF binding to TrKA on PC12 cells. Neuron 1994; 13: 203–215.CrossRefGoogle Scholar
125Davies, AM, Lee, K-F, Jaenisch, R. p75-deficient trigeminal sensory neurons have an altered response to NGF but not to other neurotrophins. Neuron 1993; 11: 565–574.CrossRefGoogle ScholarPubMed
126Rabizadeh, S, Oh, J, Zhong, LT. et al. Induction of apoptosis by the low-affinity NGF receptor. Science 1993; 261: 345–348.CrossRefGoogle ScholarPubMed
127Van der Zee, CEEM, Ross, GM, Riopelle, RJ, Hagg, T. Survival of cholinergic forebrain neurons in developing p75NGFR-deficient mice. Science 1996; 274: 1729–1732.CrossRefGoogle ScholarPubMed
128Feinstein, E, Kimchi, A, Wallach, D, Boldin, M, Varfolomeev, E. The death domain: a module shared by proteins with diverse cellular functions. Trends Biochem Sci 1995; 20: 342–344.CrossRefGoogle ScholarPubMed
129Anton, ES, Weskamp, G, Reichardt, LF, Matthew, WD. Proc Natl Acad Sci USA 1994; 91: 2795–2799.CrossRefGoogle Scholar
130Petrij, F, Giles, RH, Dauwerse, HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 1995; 376 (6538): 348–351.CrossRefGoogle ScholarPubMed
131Trivier, E, De Cesare, D, Jacquot, S, et al. Mutations in the kinse Rsk-2 associated with Coffin-Lowry syndrome. Nature 1996; 384: 567–570.CrossRefGoogle Scholar