Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms

Science

Volumn 286, Issue 5443, 1999, Pages 1358-1362

  Bonni, Azad ^a   Brunet, Anne ^a   West, Anne E ^a   Datta, Sandeep Robert ^a   Takasu, Mari A ^a   Greenberg, Michael E ^a  

^a HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE; RAS PROTEIN;

ANIMAL CELL; APOPTOSIS; ARTICLE; CELL DEATH; CELL SURVIVAL; CONTROLLED STUDY; GENE FUNCTION; GENE INACTIVATION; GENETIC TRANSCRIPTION; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; REGULATORY MECHANISM; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; BCL-ASSOCIATED DEATH PROTEIN; BRAIN-DERIVED NEUROTROPHIC FACTOR; CARRIER PROTEINS; CELL SURVIVAL; CELLS, CULTURED; CEREBELLUM; CYCLIC AMP RESPONSE ELEMENT-BINDING PROTEIN; ENZYME ACTIVATION; ENZYME INHIBITORS; FLAVONOIDS; INSULIN-LIKE GROWTH FACTOR I; MAP KINASE KINASE 1; MAP KINASE SIGNALING SYSTEM; MITOGEN-ACTIVATED PROTEIN KINASE KINASES; MITOGEN-ACTIVATED PROTEIN KINASES; MUTATION; NEURONS; PHOSPHORYLATION; PHOSPHOSERINE; PROTEIN-SERINE-THREONINE KINASES; RAS PROTEINS; RATS; RATS, LONG-EVANS; RECOMBINANT FUSION PROTEINS; RIBOSOMAL PROTEIN S6 KINASES; TRANSCRIPTION, GENETIC; TRANSFECTION;

EID: 0032698075     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.286.5443.1358     Document Type: Article

References (80)

1. J. F. R. Kerr, A. H. Wyllie, A. R. Currle, Br. J. Cancer 26, 239 (1972); H. Steller, Science 267, 1445 (1995); M. D. Jacobson, M. Weil, M. C. Raff, Cell 88, 347 (1997); D. L. Vaux and S. J. Korsmeyer, Cell 96, 245 (1999).
2. J. F. R. Kerr, A. H. Wyllie, A. R. Currle, Br. J. Cancer 26, 239 (1972); H. Steller, Science 267, 1445 (1995); M. D. Jacobson, M. Weil, M. C. Raff, Cell 88, 347 (1997); D. L. Vaux and S. J. Korsmeyer, Cell 96, 245 (1999).
3. J. F. R. Kerr, A. H. Wyllie, A. R. Currle, Br. J. Cancer 26, 239 (1972); H. Steller, Science 267, 1445 (1995); M. D. Jacobson, M. Weil, M. C. Raff, Cell 88, 347 (1997); D. L. Vaux and S. J. Korsmeyer, Cell 96, 245 (1999).
4. J. F. R. Kerr, A. H. Wyllie, A. R. Currle, Br. J. Cancer 26, 239 (1972); H. Steller, Science 267, 1445 (1995); M. D. Jacobson, M. Weil, M. C. Raff, Cell 88, 347 (1997); D. L. Vaux and S. J. Korsmeyer, Cell 96, 245 (1999).
5. G. D. Borasio et al., Neuron 2, 1087 (1989); C. D. Nobes and A. M. Tolkovsky, Eur. J. Neurosci. 7, 344 (1995); K. S. Vogel, C. I. Brannan, N. A. Jenkins, N. G. Copeland, L. F. Parada, Cell 82, 733 (1995); J. Downward, Curr. Opin. Genet. Dev. 8, 49 (1998); S. R. Datta and M. E. Greenberg, Hormones Signal. 1, 257 (1998).
6. G. D. Borasio et al., Neuron 2, 1087 (1989); C. D. Nobes and A. M. Tolkovsky, Eur. J. Neurosci. 7, 344 (1995); K. S. Vogel, C. I. Brannan, N. A. Jenkins, N. G. Copeland, L. F. Parada, Cell 82, 733 (1995); J. Downward, Curr. Opin. Genet. Dev. 8, 49 (1998); S. R. Datta and M. E. Greenberg, Hormones Signal. 1, 257 (1998).
7. G. D. Borasio et al., Neuron 2, 1087 (1989); C. D. Nobes and A. M. Tolkovsky, Eur. J. Neurosci. 7, 344 (1995); K. S. Vogel, C. I. Brannan, N. A. Jenkins, N. G. Copeland, L. F. Parada, Cell 82, 733 (1995); J. Downward, Curr. Opin. Genet. Dev. 8, 49 (1998); S. R. Datta and M. E. Greenberg, Hormones Signal. 1, 257 (1998).
8. G. D. Borasio et al., Neuron 2, 1087 (1989); C. D. Nobes and A. M. Tolkovsky, Eur. J. Neurosci. 7, 344 (1995); K. S. Vogel, C. I. Brannan, N. A. Jenkins, N. G. Copeland, L. F. Parada, Cell 82, 733 (1995); J. Downward, Curr. Opin. Genet. Dev. 8, 49 (1998); S. R. Datta and M. E. Greenberg, Hormones Signal. 1, 257 (1998).
9. G. D. Borasio et al., Neuron 2, 1087 (1989); C. D. Nobes and A. M. Tolkovsky, Eur. J. Neurosci. 7, 344 (1995); K. S. Vogel, C. I. Brannan, N. A. Jenkins, N. G. Copeland, L. F. Parada, Cell 82, 733 (1995); J. Downward, Curr. Opin. Genet. Dev. 8, 49 (1998); S. R. Datta and M. E. Greenberg, Hormones Signal. 1, 257 (1998).
10. P. Meier and G. Evan, Cell 95, 295 (1998).
11. P. Kurada and K. White, Cell 95, 319 (1998); A. Bergmann, J. Agapite, K. McCall, H. Steller, Cell 95, 331 (1998).
12. P. Kurada and K. White, Cell 95, 319 (1998); A. Bergmann, J. Agapite, K. McCall, H. Steller, Cell 95, 331 (1998).
13. Z. Xia, M. Dickens, J. Raingeaud, R. J. Davis, M. E. Greenberg, Science 270, 1326 (1995); A. Meyer-Franke et al., Neuron 21, 681 (1998).
14. Z. Xia, M. Dickens, J. Raingeaud, R. J. Davis, M. E. Greenberg, Science 270, 1326 (1995); A. Meyer-Franke et al., Neuron 21, 681 (1998).
15. M. O. Hengartner and H. R. Horvltz, Curr. Opin. Genet. Dev. 4, 481 (1994); C. B. Thompson, Science 267, 1456 (1995); J. C. Reed, Adv. Pharmacol. 41, 501 (1997); D. T. Chao and S. J. Korsmeyer, Annu. Rev. Immunol. 16, 395 (1998); J. M. Adams and S. Cory, Science 281, 1322 (1998).
16. M. O. Hengartner and H. R. Horvltz, Curr. Opin. Genet. Dev. 4, 481 (1994); C. B. Thompson, Science 267, 1456 (1995); J. C. Reed, Adv. Pharmacol. 41, 501 (1997); D. T. Chao and S. J. Korsmeyer, Annu. Rev. Immunol. 16, 395 (1998); J. M. Adams and S. Cory, Science 281, 1322 (1998).
17. M. O. Hengartner and H. R. Horvltz, Curr. Opin. Genet. Dev. 4, 481 (1994); C. B. Thompson, Science 267, 1456 (1995); J. C. Reed, Adv. Pharmacol. 41, 501 (1997); D. T. Chao and S. J. Korsmeyer, Annu. Rev. Immunol. 16, 395 (1998); J. M. Adams and S. Cory, Science 281, 1322 (1998).
18. M. O. Hengartner and H. R. Horvltz, Curr. Opin. Genet. Dev. 4, 481 (1994); C. B. Thompson, Science 267, 1456 (1995); J. C. Reed, Adv. Pharmacol. 41, 501 (1997); D. T. Chao and S. J. Korsmeyer, Annu. Rev. Immunol. 16, 395 (1998); J. M. Adams and S. Cory, Science 281, 1322 (1998).
19. M. O. Hengartner and H. R. Horvltz, Curr. Opin. Genet. Dev. 4, 481 (1994); C. B. Thompson, Science 267, 1456 (1995); J. C. Reed, Adv. Pharmacol. 41, 501 (1997); D. T. Chao and S. J. Korsmeyer, Annu. Rev. Immunol. 16, 395 (1998); J. M. Adams and S. Cory, Science 281, 1322 (1998).
20. X. Liu, C. N. Kim, J. Yang, R. Jemerson, X. Wang, Cell 86, 147 (1996); D. R. Green and J. C. Reed, Science 281, 1305 (1998); N. A. Thornberry and Y. Lazebnik, Science 281, 1312 (1998).
21. X. Liu, C. N. Kim, J. Yang, R. Jemerson, X. Wang, Cell 86, 147 (1996); D. R. Green and J. C. Reed, Science 281, 1305 (1998); N. A. Thornberry and Y. Lazebnik, Science 281, 1312 (1998).
22. X. Liu, C. N. Kim, J. Yang, R. Jemerson, X. Wang, Cell 86, 147 (1996); D. R. Green and J. C. Reed, Science 281, 1305 (1998); N. A. Thornberry and Y. Lazebnik, Science 281, 1312 (1998).
23. L. Minichiello and R. Klein, Genes Dev. 15, 2849 (1996); P. M. Schwartz, P. R. Borghesani, R. L. Levy, S. L. Pomeroy, R. A. Segal, Neuron 19, 269 (1997).
24. L. Minichiello and R. Klein, Genes Dev. 15, 2849 (1996); P. M. Schwartz, P. R. Borghesani, R. L. Levy, S. L. Pomeroy, R. A. Segal, Neuron 19, 269 (1997).
25. R. A. Segal, H. Takahashi, R. D. McKay, Neuron 9, 1041 (1992); D. Lindholm, G. Dechant, C. P. Heisenberg, H. Thoenen, Eur. J. Neurosci. 5, 1455 (1993); T. Kubo, T. Nonomura, Y. Enokido, H. Hatanaka, Dev. Brain Res. 85, 249 (1995).
26. R. A. Segal, H. Takahashi, R. D. McKay, Neuron 9, 1041 (1992); D. Lindholm, G. Dechant, C. P. Heisenberg, H. Thoenen, Eur. J. Neurosci. 5, 1455 (1993); T. Kubo, T. Nonomura, Y. Enokido, H. Hatanaka, Dev. Brain Res. 85, 249 (1995).
27. R. A. Segal, H. Takahashi, R. D. McKay, Neuron 9, 1041 (1992); D. Lindholm, G. Dechant, C. P. Heisenberg, H. Thoenen, Eur. J. Neurosci. 5, 1455 (1993); T. Kubo, T. Nonomura, Y. Enokido, H. Hatanaka, Dev. Brain Res. 85, 249 (1995).
28. Cerebellar granule cultures were prepared as described (15). Cerebellar granule neurons were cultured from Long-Evans rats on postnatal day 6, Neurons were placed on polyomithine-coated plates and grown in basal medium Eagle (BME, Sigma) supplemented with calf serum (10%) (Hyclone), 25 mM KCl, 2 mM glutamine, penicillin, and streptomycin. One day after cultures were prepared (P6 + 1 DIV), they were treated with the antimitotic agent cytosine-β-D-arabinofuranoside (10 μM) to prevent cell proliferation. For the assessment of cell survival in the absence or presence of inhibitors, P6 + 5 DIV cultures were washed twice with medium (BME) containing 5 mM KCl and no serum (starvation medium) and then placed in this medium in the presence or absence of the survival factor (BDNF, insulin, or ICF-1) and in the presence of MAPK, PI-3K inhibitors, or their vehicle, dimethyl sulfoxide (DMSO). In experiments in which biochemical analyses were done, the medium [BME + calf serum (10%) + 25 mM KCl] was switched to starvation medium 1 hour before stimulation with the survival factor. In the last 30 min of the 1-hour starvation period, the inhibitor or its vehicle control (DMSO) was added.
29. Immunoblotting was carried out as described (31, 38). Briefly, proteins from lysates were separated by poly-acrylamide gel electrophoresis (PAGE), transferred to nitrocellulose membranes, and immunoblotted with the appropriate primary antibody. Antibody binding was detected by enhanced chemiluminescence (ECL, Amersham) with a secondary antibody conjugated to horseradish peroxidase (dilution: 1:20,000).
30. 5 cells. In the experiments shown in Fig. 3C, cultures were transfected with 0.5 μg of the test plasmid and 0.5 μg of the β-galactosidase expression plasmid per well of a 24-well plate. In Fig. 3A, each well was transfected with 1.5 μg of MEK-1ca, 0.05 μg of the BAD or BAD5112A expression plasmid, and 0.5 μg of the β-galactosidase expression plasmid. In Fig. 3B, each well was transfected with 1.5 μg of MEK-1ca with 1 μg of Rsk2-WT or Rsk2-KN [Rsk2KR100 (32)], 0.125 μg of the BAD or BADS112A expression plasmid, and 0.5 μg of the β-galactosidase expression plasmid.
31. Indirect immunofluorescence was done as described [A. Bonni, D. A. Frank, C. Schindler, M. E. Greenberg, Science 262, 1575 (1993)]. Cultures were fixed in 4% paraformaldehyde and subjected to indirect immunofluorescence with a mouse monoclonal antibody (mAb) to β-galactosidase (Promega, dilution 1: 500) and the DNA dye bisbenzimide (Hoechst 33258). Determination of cell death in neurons was made on the basis of integrity of neurites and nuclear morphology. Cell counts were carried out in a blinded manner by two independent observers.
32. S. R. D'Mello, C. Galli, T. Ciotti, P. Calissano, Proc. Natl. Acad. Acad. Sci. U.S.A. 90, 10989 (1993).
33. H. Dudek et al., Science 275, 661 (1997).
34. A. Bonni et al., unpublished data.
35. D. R. Alessi et al., EMBO J. 15, 6541 (1996).
36. A. D. Kohn, K. S. Kovacina, R. A. Roth, EMBO J. 14, 4288 (1995); C. J. Kowalski, E. D. Schneiderman, S. M. Willis, Int. J. Biomed. Comput. 37, 273 (1994); A. Kauffmann-Zeh et al., Nature 385, 544 (1997); S. R. D'Mello, K. Borodezt, S. P. Soltoff J. Neurosci. 17, 1548 (1997); S. G. Kennedy et al., Genes Dev. 11, 701 (1997); G. Kulik and M. J. Weber, Mol. Cell. Biol. 18, 6711 (1998).
37. A. D. Kohn, K. S. Kovacina, R. A. Roth, EMBO J. 14, 4288 (1995); C. J. Kowalski, E. D. Schneiderman, S. M. Willis, Int. J. Biomed. Comput. 37, 273 (1994); A. Kauffmann-Zeh et al., Nature 385, 544 (1997); S. R. D'Mello, K. Borodezt, S. P. Soltoff J. Neurosci. 17, 1548 (1997); S. G. Kennedy et al., Genes Dev. 11, 701 (1997); G. Kulik and M. J. Weber, Mol. Cell. Biol. 18, 6711 (1998).
38. A. D. Kohn, K. S. Kovacina, R. A. Roth, EMBO J. 14, 4288 (1995); C. J. Kowalski, E. D. Schneiderman, S. M. Willis, Int. J. Biomed. Comput. 37, 273 (1994); A. Kauffmann-Zeh et al., Nature 385, 544 (1997); S. R. D'Mello, K. Borodezt, S. P. Soltoff J. Neurosci. 17, 1548 (1997); S. G. Kennedy et al., Genes Dev. 11, 701 (1997); G. Kulik and M. J. Weber, Mol. Cell. Biol. 18, 6711 (1998).
39. A. D. Kohn, K. S. Kovacina, R. A. Roth, EMBO J. 14, 4288 (1995); C. J. Kowalski, E. D. Schneiderman, S. M. Willis, Int. J. Biomed. Comput. 37, 273 (1994); A. Kauffmann-Zeh et al., Nature 385, 544 (1997); S. R. D'Mello, K. Borodezt, S. P. Soltoff J. Neurosci. 17, 1548 (1997); S. G. Kennedy et al., Genes Dev. 11, 701 (1997); G. Kulik and M. J. Weber, Mol. Cell. Biol. 18, 6711 (1998).
40. A. D. Kohn, K. S. Kovacina, R. A. Roth, EMBO J. 14, 4288 (1995); C. J. Kowalski, E. D. Schneiderman, S. M. Willis, Int. J. Biomed. Comput. 37, 273 (1994); A. Kauffmann-Zeh et al., Nature 385, 544 (1997); S. R. D'Mello, K. Borodezt, S. P. Soltoff J. Neurosci. 17, 1548 (1997); S. G. Kennedy et al., Genes Dev. 11, 701 (1997); G. Kulik and M. J. Weber, Mol. Cell. Biol. 18, 6711 (1998).
41. A. D. Kohn, K. S. Kovacina, R. A. Roth, EMBO J. 14, 4288 (1995); C. J. Kowalski, E. D. Schneiderman, S. M. Willis, Int. J. Biomed. Comput. 37, 273 (1994); A. Kauffmann-Zeh et al., Nature 385, 544 (1997); S. R. D'Mello, K. Borodezt, S. P. Soltoff J. Neurosci. 17, 1548 (1997); S. G. Kennedy et al., Genes Dev. 11, 701 (1997); G. Kulik and M. J. Weber, Mol. Cell. Biol. 18, 6711 (1998).
42. J. Zha, H. Harada, E. Yang, J. Jocket, S. J. Korsmeyer, Cell 87, 619 (1996).
43. S. R. Datta et al., Cell 91, 231 (1997).
44. L. del Peso, M. González-García, C. Page, R. Herrera, G. Nuñez, Science 278, 687 (1997); P. Blume-Jensen, R. Janknecht, T. Hunter, Curr. Biol. 8, 779 (1998).
45. L. del Peso, M. González-García, C. Page, R. Herrera, G. Nuñez, Science 278, 687 (1997); P. Blume-Jensen, R. Janknecht, T. Hunter, Curr. Biol. 8, 779 (1998).
46. H. Harada et al., Mol. Cell 3, 413 (1999).
47. J. Blenis, Proc. Natl. Acad. Sci. U.S.A. 90, 5889 (1993); D. R. Alessi et al., FEBS Lett. 399, 333 (1996).
48. J. Blenis, Proc. Natl. Acad. Sci. U.S.A. 90, 5889 (1993); D. R. Alessi et al., FEBS Lett. 399, 333 (1996).
49. 136).
50. 112 (11, 26).
51. 112 was confirmed by its reactivity to recombinant BAD protein that was phosphorylated by PKA but not to unphosphorylated BAD, and by its recognition of Rsk2-or PKA-induced phosphorylated wild-type BAD but not S112A BAD that was expressed in 293T cells.
52. J. Xing, J. M. Kornhauser, Z. Xia, E. A. Thiele, M. E. Greenberg, Mol. Cell. Biol. 18, 1946 (1998); S. Finkbeiner et al., Neuron 19, 1031 (1997).
53. J. Xing, J. M. Kornhauser, Z. Xia, E. A. Thiele, M. E. Greenberg, Mol. Cell. Biol. 18, 1946 (1998); S. Finkbeiner et al., Neuron 19, 1031 (1997).
54. J. Xing and M. E. Greenberg, unpublished data.
55. C. S. Hill and R. Treisman, Cell 80, 199 (1995); R. Treisman, Curr. Opin. Cell Biol. 8, 205 (1996); B. Su and M. Karin, Curr. Opin. Immunol. 8, 402 (1996); R. A. Segal and M. E. Greenberg, Annu. Rev. Neurosci. 19, 463 (1996); A. Bonni and M. E. Greenberg, Can. J. Neurol. Sci. 24, 272 (1997); B. Wasytyk, J. Hagman, A. Gutierrez-Hartmann, Trends Biochem. Sci. 23, 213 (1993); A. J. Shaywitz and M. E. Greenberg, Annu. Rev. Biochem. 68, 821 (1999).
56. C. S. Hill and R. Treisman, Cell 80, 199 (1995); R. Treisman, Curr. Opin. Cell Biol. 8, 205 (1996); B. Su and M. Karin, Curr. Opin. Immunol. 8, 402 (1996); R. A. Segal and M. E. Greenberg, Annu. Rev. Neurosci. 19, 463 (1996); A. Bonni and M. E. Greenberg, Can. J. Neurol. Sci. 24, 272 (1997); B. Wasytyk, J. Hagman, A. Gutierrez-Hartmann, Trends Biochem. Sci. 23, 213 (1993); A. J. Shaywitz and M. E. Greenberg, Annu. Rev. Biochem. 68, 821 (1999).
57. C. S. Hill and R. Treisman, Cell 80, 199 (1995); R. Treisman, Curr. Opin. Cell Biol. 8, 205 (1996); B. Su and M. Karin, Curr. Opin. Immunol. 8, 402 (1996); R. A. Segal and M. E. Greenberg, Annu. Rev. Neurosci. 19, 463 (1996); A. Bonni and M. E. Greenberg, Can. J. Neurol. Sci. 24, 272 (1997); B. Wasytyk, J. Hagman, A. Gutierrez-Hartmann, Trends Biochem. Sci. 23, 213 (1993); A. J. Shaywitz and M. E. Greenberg, Annu. Rev. Biochem. 68, 821 (1999).
58. C. S. Hill and R. Treisman, Cell 80, 199 (1995); R. Treisman, Curr. Opin. Cell Biol. 8, 205 (1996); B. Su and M. Karin, Curr. Opin. Immunol. 8, 402 (1996); R. A. Segal and M. E. Greenberg, Annu. Rev. Neurosci. 19, 463 (1996); A. Bonni and M. E. Greenberg, Can. J. Neurol. Sci. 24, 272 (1997); B. Wasytyk, J. Hagman, A. Gutierrez-Hartmann, Trends Biochem. Sci. 23, 213 (1993); A. J. Shaywitz and M. E. Greenberg, Annu. Rev. Biochem. 68, 821 (1999).
59. C. S. Hill and R. Treisman, Cell 80, 199 (1995); R. Treisman, Curr. Opin. Cell Biol. 8, 205 (1996); B. Su and M. Karin, Curr. Opin. Immunol. 8, 402 (1996); R. A. Segal and M. E. Greenberg, Annu. Rev. Neurosci. 19, 463 (1996); A. Bonni and M. E. Greenberg, Can. J. Neurol. Sci. 24, 272 (1997); B. Wasytyk, J. Hagman, A. Gutierrez-Hartmann, Trends Biochem. Sci. 23, 213 (1993); A. J. Shaywitz and M. E. Greenberg, Annu. Rev. Biochem. 68, 821 (1999).
60. C. S. Hill and R. Treisman, Cell 80, 199 (1995); R. Treisman, Curr. Opin. Cell Biol. 8, 205 (1996); B. Su and M. Karin, Curr. Opin. Immunol. 8, 402 (1996); R. A. Segal and M. E. Greenberg, Annu. Rev. Neurosci. 19, 463 (1996); A. Bonni and M. E. Greenberg, Can. J. Neurol. Sci. 24, 272 (1997); B. Wasytyk, J. Hagman, A. Gutierrez-Hartmann, Trends Biochem. Sci. 23, 213 (1993); A. J. Shaywitz and M. E. Greenberg, Annu. Rev. Biochem. 68, 821 (1999).
61. C. S. Hill and R. Treisman, Cell 80, 199 (1995); R. Treisman, Curr. Opin. Cell Biol. 8, 205 (1996); B. Su and M. Karin, Curr. Opin. Immunol. 8, 402 (1996); R. A. Segal and M. E. Greenberg, Annu. Rev. Neurosci. 19, 463 (1996); A. Bonni and M. E. Greenberg, Can. J. Neurol. Sci. 24, 272 (1997); B. Wasytyk, J. Hagman, A. Gutierrez-Hartmann, Trends Biochem. Sci. 23, 213 (1993); A. J. Shaywitz and M. E. Greenberg, Annu. Rev. Biochem. 68, 821 (1999).
62. J. Xing, D. D. Ginty, M. E. Greenberg, Science 273, 959 (1996); D. De Cesare, S. Jacquot, A. Hanauer, P. Sassone-Corsi, Proc. Natl. Acad. Sci. U.S.A. 13, 12202 (1998).
63. J. Xing, D. D. Ginty, M. E. Greenberg, Science 273, 959 (1996); D. De Cesare, S. Jacquot, A. Hanauer, P. Sassone-Corsi, Proc. Natl. Acad. Sci. U.S.A. 13, 12202 (1998).
64. D. D. Ginty, A. Bonni, M. E. Greenberg, Cell 77, 713 (1994); A. Bonni, D. D. Ginty, H. Dudek, M. E. Greenberg, Mol. Cell. Neurosci. 6, 168 (1995).
65. D. D. Ginty, A. Bonni, M. E. Greenberg, Cell 77, 713 (1994); A. Bonni, D. D. Ginty, H. Dudek, M. E. Greenberg, Mol. Cell. Neurosci. 6, 168 (1995).
66. K. M. Walton, R. P. Rehfuss, J. C. Chrivia, J. E. Lochner, R. H. Goodman, Mol. Endocrinol. 6, 647 (1992); G. A. Gonzalez and M. R. Montminy, Cell 59, 675 (1989).
67. K. M. Walton, R. P. Rehfuss, J. C. Chrivia, J. E. Lochner, R. H. Goodman, Mol. Endocrinol. 6, 647 (1992); G. A. Gonzalez and M. R. Montminy, Cell 59, 675 (1989).
68. A. Riccio et al., in preparation; B. I. Wilson, E. Mochon, L. M. Boxer, Mol. Cell. Biol. 16, 5546 (1996).
69. A. Riccio et al., in preparation; B. I. Wilson, E. Mochon, L. M. Boxer, Mol. Cell. Biol. 16, 5546 (1996).
70. D. A. Frank and M. E. Greenberg, Cell 79, 5 (1994); J. C. Yin, M. Del Vecchio, H. Zhou, T. Tully, Cell 81, 107 (1995); R. Bourtchuladze et al., Cell 79, 59 (1994); J. C. P. Yin et al., Cell 79, 49 (1994); K. Deisseroth, H. Bito, R. W. Tsien, Neuron 16, 89 (1996); A. J. Silva, J. H. Kogan, P. W. Frankland, S. Kida, Annu. Rev. Neurosci. 21, 127 (1998).
71. D. A. Frank and M. E. Greenberg, Cell 79, 5 (1994); J. C. Yin, M. Del Vecchio, H. Zhou, T. Tully, Cell 81, 107 (1995); R. Bourtchuladze et al., Cell 79, 59 (1994); J. C. P. Yin et al., Cell 79, 49 (1994); K. Deisseroth, H. Bito, R. W. Tsien, Neuron 16, 89 (1996); A. J. Silva, J. H. Kogan, P. W. Frankland, S. Kida, Annu. Rev. Neurosci. 21, 127 (1998).
72. D. A. Frank and M. E. Greenberg, Cell 79, 5 (1994); J. C. Yin, M. Del Vecchio, H. Zhou, T. Tully, Cell 81, 107 (1995); R. Bourtchuladze et al., Cell 79, 59 (1994); J. C. P. Yin et al., Cell 79, 49 (1994); K. Deisseroth, H. Bito, R. W. Tsien, Neuron 16, 89 (1996); A. J. Silva, J. H. Kogan, P. W. Frankland, S. Kida, Annu. Rev. Neurosci. 21, 127 (1998).
73. D. A. Frank and M. E. Greenberg, Cell 79, 5 (1994); J. C. Yin, M. Del Vecchio, H. Zhou, T. Tully, Cell 81, 107 (1995); R. Bourtchuladze et al., Cell 79, 59 (1994); J. C. P. Yin et al., Cell 79, 49 (1994); K. Deisseroth, H. Bito, R. W. Tsien, Neuron 16, 89 (1996); A. J. Silva, J. H. Kogan, P. W. Frankland, S. Kida, Annu. Rev. Neurosci. 21, 127 (1998).
74. D. A. Frank and M. E. Greenberg, Cell 79, 5 (1994); J. C. Yin, M. Del Vecchio, H. Zhou, T. Tully, Cell 81, 107 (1995); R. Bourtchuladze et al., Cell 79, 59 (1994); J. C. P. Yin et al., Cell 79, 49 (1994); K. Deisseroth, H. Bito, R. W. Tsien, Neuron 16, 89 (1996); A. J. Silva, J. H. Kogan, P. W. Frankland, S. Kida, Annu. Rev. Neurosci. 21, 127 (1998).
75. D. A. Frank and M. E. Greenberg, Cell 79, 5 (1994); J. C. Yin, M. Del Vecchio, H. Zhou, T. Tully, Cell 81, 107 (1995); R. Bourtchuladze et al., Cell 79, 59 (1994); J. C. P. Yin et al., Cell 79, 49 (1994); K. Deisseroth, H. Bito, R. W. Tsien, Neuron 16, 89 (1996); A. J. Silva, J. H. Kogan, P. W. Frankland, S. Kida, Annu. Rev. Neurosci. 21, 127 (1998).
76. D. Rudolph et al., Proc. Natl. Acad. Natl. Sci. U.S.A. 95, 4481 (1998).
77. J. P. Somers, J. A. DeLoia, A. J. Zeleznik, Mol. Endocrinol. 13, 1364 (1999).
78. A. Shimamura et al., in preparation.
79. A. Brunet et al., Cell 96, 857 (1999).
80. We thank A. Shaywitz, Y. Gotoh, and other members of the Greenberg laboratory for helpful discussions, M. Weber for mAb B3B9, L Boxer for bd-2 promoter plasmids, R. Goodman for CREB plasmids, S. Vasquez for technical assistance, and S. Chang and E. Chapin for their involvement in the early phase of this study. Supported by NIH PO1 grant HD 24926, Mental Retardation Research Center grant NIHP30-HD18655, and the F. M. Kirby Foundation (M.E.G.); a Howard Hughes Medical Institute postdoctoral research fellowship for physicians (A. Bonni); a Human Frontier Long-Term Fellowship (A. Brunet); and a postdoctoral National Research Service Award (A.E.W.).