Abstract
The retinoblastoma protein (pRB) is thought to suppress tumorigenesis, in part, through interactions with E2F transcription factors. However, certain low penetrance pRB mutants substantially reduce tumor incidence despite having a minimal ability to bind E2F. These low penetrance mutants retain the ability to induce a senescence-like state, suggesting that they may suppress tumorigenesis through a senescence-associated process. Here, we identify a novel pRB function that is associated with senescence and which is retained by non-E2F binding low penetrance pRB mutants. It was found that pRB and these mutants substantially increased the production of PML nuclear bodies (NBs). In keeping with the role of PML in transcriptional repression, pRB also promoted PML-dependent transcriptional repression by the c-Myc antagonist Mad1. In a series of pRB-p130 chimeric proteins, the ability to increase NB production correlated with the ability to induce a senescence-like phenotype. However, neither NB formation nor PML function were required for pRB to induce the senescence-like response. Together, these observations indicate that a pRB-induced increase in PML NB formation is coordinated with, but separable from, the pRB-induced senescence program. The data further suggest that PML may contribute to an E2F-independent tumor suppressor function of pRB.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Alcalay M, Tomassoni L, Colombo E, Stoldt S, Grignani F, Fagioli M, Szekely L, Helin K, Pelicci PG . 1998 Mol. Cell. Biol. 18: 1084–1093
Alexander K, Hinds PW . 2001 Mol. Cell. Biol. 21: 3616–3631
Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, Reed S, Sicinski P, Bartek J, Eilers M . 1999 EMBO J. 18: 5321–5333
Bremner R, Du DC, Connolly-Wilson MJ, Bridge P, Ahmad KF, Mostachfi H, Rushlow D, Dunn JM, Gallie BL . 1997 Am. J. Hum. Genet. 61: 556–570
Cheng L, Rossi F, Fang W, Mori T, Cobrinik D . 2000 J. Biol. Chem. 275: 30317–30325
de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A . 1991 Cell 66: 675–684
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano E, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J . 1995 Proc. Natl. Acad. Sci. USA 92: 9363–9367
Fagioli M, Alcalay M, Pandolfi PP, Venturini L, Mencarelli A, Simeone A, Acampora D, Grignani F, Pelicci PG . 1992 Oncogene 7: 1083–1091
Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, Lowe SW . 2000 Genes Dev. 14: 2015–2027
Gottifredi V, Prives C . 2001 Trends Cell Biol. 11: 184–187
Grandori C, Cowley SM, James LP, Eisenman RN . 2000 Annu. Rev. Cell Dev. Biol. 16: 653–699
Guo A, Salomoni P, Luo J, Shih A, Zhong G, Gu W, Pandolfi PP . 2000 Nat. Cell Biol. 2: 730–736
Hannon GJ, Demetrick D, Beach D . 1993 Genes Dev. 7: 2378–2391
Harbour JW . 2001 Arch. Ophthalmol. 119: 1699–1704
Harbour JW, Dean DC . 2001 Curr. Top. Microbiol. Immunol. 254: 137–144
Harbour JW, Lai SL, Whang-Peng J, Gazdar AF, Minna JD, Kaye FJ . 1988 Science 241: 353–357
Horowitz JM, Park SH, Bogenmann E, Cheng JC, Yandell DW, Kaye FJ, Minna JD, Dryja TP, Weinberg RA . 1990 Proc. Natl. Acad. Sci. USA 87: 2775–2779
Jensen K, Shiels C, Freemont PS . 2001 Oncogene 20: 7223–7233
Jiang WQ, Ringertz N . 1997 Cell Growth Differ. 8: 513–522
Kakizuka A, Miller Jr WH, Umesono K, Warrell Jr RP, Frankel SR, Murty VV, Dmitrovsky E, Evans RM . 1991 Cell 66: 663–674
Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub MP, Durand B, Lanotte M, Berger R, Chambon P . 1992 EMBO J. 11: 629–642
Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T, Ichikawa-Iwata E, Zhong S, Pandolfi PP, Ishii S . 2001a Mol. Cell 7: 1233–1243
Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Zhong S, Pandolfi PP, Ishii S . 2001b J. Biol. Chem. 276: 43491–43494
Koken MH, Linares-Cruz G, Quignon F, Viron A, Chelbi-Alix MK, Sobczak-Thepot J, Juhlin L, Degos L, Calvo F, de The H . 1995 Oncogene 10: 1315–1324
Kratzke RA, Otterson GA, Hogg A, Coxon AB, Geradts J, Cowell JK, Kaye FJ . 1994 Oncogene 9: 1321–1326
Le XF, Yang P, Chang KS . 1996 J. Biol. Chem. 271: 130–135
Lin RJ, Sternsdorf T, Tini M, Evans RM . 2001 Oncogene 20: 7204–7215
Liu JH, Mu ZM, Chang KS . 1995 J. Exp. Med. 181: 1965–1973
Maul GG, Negorev D, Bell P, Ishov AM . 2000 J. Struct. Biol. 129: 278–287
Morgenstern JP, Land H . 1990 Nucleic Acids Res. 18: 3587–3588
Mu ZM, Chin KV, Liu JH, Lozano G, Chang KS . 1994 Mol. Cell. Biol. 14: 6858–6867
Muller S, Matunis MJ, Dejean A . 1998 EMBO J. 17: 61–70
Negorev D, Maul GG . 2001 Oncogene 20: 7234–7242
Otterson GA, Chen W, Coxon AB, Khleif SN, Kaye FJ . 1997 Proc. Natl. Acad. Sci. USA 94: 12036–12040
Otterson GA, Modi S, Nguyen K, Coxon AB, Kaye FJ . 1999 Am. J. Hum. Genet. 65: 1040–1046
Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S, Higashimoto Y, Appella E, Minucci S, Pandolfi PP, Pelicci PG . 2000 Nature 406: 207–210
Piazza F, Gurrieri C, Pandolfi PP . 2001 Oncogene 20: 7216–7222
Qian Y, Luckey C, Horton L, Esser M, Templeton DJ . 1992 Mol. Cell. Biol. 12: 5363–5372
Qin XQ, Chittenden T, Livingston DM, Kaelin Jr WG . 1992 Genes Dev. 6: 953–964
Quignon F, De Bels F, Koken M, Feunteun J, Ameisen JC, de The H . 1998 Nat. Genet. 20: 259–265
Rego EM, Wang ZG, Peruzzi D, He LZ, Cordon-Cardo C, Pandolfi PP . 2001 J. Exp. Med. 193: 521–529
Sellers WR, Novitch BG, Miyake S, Heith A, Otterson GA, Kaye FJ, Lassar AB, Kaelin WG . 1998 Genes Dev. 12: 95–106
Shinagawa T, Dong HD, Xu M, Maekawa T, Ishii S . 2000 EMBO J. 19: 2280–2291
Sternsdorf T, Jensen K, Will H . 1997 J. Cell Biol. 139: 1621–1634
Templeton D, Park SH, Lanier L, Weinberg RA . 1991 Proc. Natl. Acad. Sci. USA 88: 3033–3037
Tokitou F, Nomura T, Khan MM, Kaul SC, Wadhwa R, Yasukawa T, Kohno I, Ishii S . 1999 J. Biol. Chem. 274: 4485–4488
van den Heuvel S, Harlow E . 1993 Science 262: 2050–2054
Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C, Grosveld F, Pandolfi PP . 1998a Science 279: 1547–1551
Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R, Pandolfi PP . 1998b Nat. Genet. 20: 266–272
Weinberg RA . 1995 Cell 81: 323–330
Wu WS, Vallian S, Seto E, Yang WM, Edmondson D, Roth S, Chang KS . 2001 Mol. Cell. Biol. 21: 2259–2268
Xu HJ, Zhou Y, Ji W, Perng GS, Kruzelock R, Kong CT, Bast RC, Mills GB, Li J, Hu SX . 1997 Oncogene 15: 2589–2596
Zhang P, Chin W, Chow LT, Chan AS, Yim AP, Leung SF, Mok TS, Chang KS, Johnson PJ, Chan JY . 2000 Int. J. Cancer 85: 599–605
Zhong S, Hu P, Ye TZ, Stan R, Ellis NA, Pandolfi PP . 1999 Oncogene 18: 7941–7947
Zhu L, van den Heuvel S, Helin K, Fattaey A, Ewen M, Livingston D, Dyson N, Harlow E . 1993 Genes Dev. 7: 1111–1125
Acknowledgements
We thank P Chambon, K-S Chang, M Eilers, F Kaye, P Whyte and L Zhu for plasmid DNAs. We also thank R Weinberg and L Zhu for critical reading of the manuscript, and D Li for technical assistance. This work was supported by grants from the James S McDonnell Foundation, the Dorothy Rodbell Cohen Foundation, and the Human Frontiers Science Program Organization to D Cobrinik and by NIH grant P30CA13696 for support of the Optical Microscopy Facility of the Herbet Irving Comprehensive Cancer Center. T Mori was supported by the Uehara Memorial Foundation and the International Society for Diseases of the Esophagus.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fang, W., Mori, T. & Cobrinik, D. Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants. Oncogene 21, 5557–5565 (2002). https://doi.org/10.1038/sj.onc.1205666
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1205666