Abstract
Rb-deficient embryos (Rb−/−) show abnormal degeneration of neurons and die at mid-gestation, suggesting that RB may protect against apoptosis. Having previously shown that cyclin D1 accumulates during K+-induced apoptosis of granule neurons, we chose to investigate the role of RB under these conditions. We show that RB is cleaved in its C-terminus during the onset of neuronal apoptosis. Caspase 3-like activity increases following K+ deprivation and the time course correlates with RB cleavage and apoptosis. Although the use of a specific caspase 3-like inhibitor (z-DEBD.fmk) delays RB cleavage and reduces DNA fragmentation, data implicate other caspases in these processes. However, K+ deprivation induces a gradual production of the active p20 subunit of caspase 3 (CPP32) that coincides with RB disappearance at the cellular level. Nuclear detection of a transfected HA-tagged caspase cleavage-resistant RB mutant (DEAG/D to DEAA/D) revealed a significant decrease in apoptosis of neurons expressing the RB mutant (less than 5%) relative to the wild type form of RB (40%) during K+ deprivation. Taken together, these data show that caspase-dependent cleavage of RB is an early permissive step of the apoptosis-inducing signaling pathway in neurons. They indicate a major role of RB in neuronal protection.
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References
Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW and Yuan J . 1996 Cell 87: 171
An B and Dou QP . 1996 Cancer Res 56: 438–442
Armstrong RC, Aja TJ, Hoang KD, Gaur S, Bai X, Alnemri ES, Litwack G, Karanewsky DS, Fritz LC and Tomaselli KJ . 1997 J Neurosci 17: 553–562
Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Juriscova A, Varmuza S, Latham KE, Flaws JA, Salter JC, Hara H, Moskowitz MA, Li E, Greenberg A, Tilly JL and Yuan J . 1998 Genes Dev 12: 1304–1314
Boussif O, Lezoualc'h F, Zanta MA, Mergny MD, Scherman D, Demeneix B and Behr JP . 1995 Proc Natl Acad Sci USA 92: 7297–7301
Boutillier AL, Kienlen-Campart P and Loeffler JP . 1999 Eur J Neurosci 11: 441–448
Campanero MR and Flemington EK . 1997 Proc Natl Acad Sci USA 94: 2221–2226
Chen J, Wu X, Lin J and Levine AJ . 1996 Mol Cell Biol 16: 2445–2452
Chen L, Marechal V, Moreau J, Levine AJ and Chen J . 1997 J Biol Chem 272: 22966–22973
Clarke AR, Maandag ER, Van Room M, Van der Lugt NM, Van der Valk M, Hooper ML, Berns A and Te Riele H . 1992 Nature 359: 328–330
D'Mello S, Galli C, Ciotti T and Calissano P . 1993 Proc Natl Acad Sci USA 90: 10989–10993
D'Mello SR, Aglieco F, Roberts MR, Borodezt K and Haycock JW . 1998 J Neurochem 70: 1809–1818
Dou QP and An B . 1998 Front Biosci 3: 419–430
Dyson N . 1998 Genes Dev 12: 2245–2262
Eldadah BA, Yakovlev AG and Faden AI . 1997 J Neurosci 17: 6105–6113
Erhardt P, Tomaselli KJ and Cooper GM . 1997 J Biol Chem 272: 15049–15052
Faleiro L, Kobayashi R, Fearnhead H and Lazebnik Y . 1997 EMBO J 16: 2271–2281
Fattman CL, An B and Dou QP . 1997 J Cell Biochem 67: 399–408
Field SJ, Tsai FY, Kuo F, Zubiaga AM, Kaelin WJ, Livingston DM, Orkin SH and Greenberg ME . 1996 Cell 85: 549–561
Friedlander RM and Yuan J . 1998 Cell Death Differ 5: 823–831
Gallo V, Kinsbury A, Balazs R and Jorgensen OS . 1987 J Neurosci 7: 2203–2213
Haas KD, Kogan SC, Levi D, Dazin P, T'Ang A, Fung YK and Israel MA . 1995 EMBO J 14: 461–472
Hateboer G, Kerkhoven RM, Shvarts A, Bernards R and Beijersbergen RL . 1996 Genes Dev 10: 2960–1970
Heintz N . 1993 Trends Biochem Sci 18: 157–159
Helin K, Holm K, Niebuhr A, Eiberg H, Tommerup N, Houggard S, Poulsen HS, Spang TM and Norgaard P . 1997 Proc Natl Acad Sci USA 94: 6933–6938
Henkart PA . 1996 Immunity 4: 195–201
Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA and Weinberg RA . 1992 Nature 359: 295–300
Janicke RU, Sprengart ML, Wati MR and Porter AG . 1998 J Biol Chem 273: 9357–9360
Janicke RU, Walker PA, Lin XY and Porter AG . 1996 EMBO J 15: 6969–6978
Kidd VJ . 1998 Annu Rev Physiol 60: 533–573
Kienlen-Campard P, Crochemore C, René F, Monnier D, Koch B and Loeffler JP . 1997 DNA & Cell Biology 16: 323–333
Kondo S, Barnett GH, Hara H, Morimura T and Takeuchi J . 1995 Oncogene 10: 2001–2006
Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P and Flavell RA . 1996 Nature 384: 368–372
Lee EY, Chang CY, Hu N, Wang YC, Lai CC, Herrup K, Lee WH and Bradley A . 1992 Nature 359: 288–294
Li H, Bergeron L, Cryns V, Pasternack MS, Zhu H, Shi L, Greenberg A and Yuan J . 1997 J Biol Chem 272: 21010–21017
Ludlow JW, DeCaprio JA, Huang CM, Lee WH, Paucha E and Livingston DM . 1989 Cell 56: 57–65
Lynch T, Vasilakos JP, Raser K, Keane KM and Shivers BD . 1997 Mol Psychiatry 2: 227–238
Magnaghi JL, Groisman R, Naguibneva I, Robin P, Lorain S, Le VJ, Troalen F, Trouche D and Harel BA . 1998 Nature 391: 601–605
Marks N, Berg MJ, Guidotti A and Saito M . 1998 J Neurosci Res 52: 334–341
Moran J, Itoh T, Reddy UR, Chen M, Alnemri ES and Pleasure D . 1999 Neurochem 73: 568–577
Nath R, Raser KJ, McGinnis K, Nadimpalli R, Stafford D and Wang KK . 1996 Neuroreport 8: 249–255
Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju SM, Smulson HE, Yamin TT, Yu VL and Miller DK . 1995 Nature 376: 37–43
Oppenheim RW . 1991 Annu Rev Neurosci 14: 453–501
Phillips AC, Bates S, Ryan KM, Helin K and Vousden KH . 1997 Genes Dev 11: 1853–1863
Prives C . 1998 Cell 95: 5–8
Schousboe A, Meier E, Drejer J and Hertz L . 1989 Preparation of cultures of mouse rat granule cells In Shahar A, De Vellis J, Vernadahis A and Haber B eds. A dissection and tissue culture manual for the nervous system New York Alan R Liss 203–206
Schulz JB, Weller M and Klockgether T . 1996 J Neurosci 16: 4696–4706
Slack RS and Miller FD . 1996 Dev Genet 18: 81–91
Sohm F, Gaiddon C, Antoine M, Boutillier AL and Loeffler JP . 1999 Oncogene 18: 2762–2769
Tan X, Martin SJ, Green DR and Wang J . 1997 J Biol Chem 272: 9613–9616
Tan X and Wang JY . 1998 Trends Cell Biol 8: 116–120
Tanabe H, Eguchi Y, Shimizu S, Martinou JC and Tsujimoto Y . 1998 Eur J Neurosci 10: 1403–1411
Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Haken A, McCurrach M, Khoo W et al. 1998 Genes Dev 12: 806–819
Xiao ZX, Chen J, Levine AJ, Modjtahedi N, Xing J, Sellers WR and Livingston DM . 1995 Nature 375: 694–698
Yuan J . 1995 Curr Opin Cell Biol 7: 211–214
Yuan J, Shaham S, Ledoux S, Ellis HM and Horvitz HR . 1993 Cell 75: 641–652
Acknowledgements
Recombinant material (pClneo-HA-RB-WT and pClneo-HA-RB-D/A) was a generous gift from Drs AG Porter and RU Jänicke (Singapore, Republic of Singapore). This work was supported by ARC (no. 9821), ‘Ligue régionale (68) pour la lutte contre le cancer’ and ‘Région Alsace’.
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Boutillier, AL., Trinh, E. & Loeffler, JP. Caspase-dependent cleavage of the retinoblastoma protein is an early step in neuronal apoptosis. Oncogene 19, 2171–2178 (2000). https://doi.org/10.1038/sj.onc.1203532
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DOI: https://doi.org/10.1038/sj.onc.1203532
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