Key Points
-
Loss of RB sensitizes cells to apoptosis.
-
Ectopic apoptosis of Rb-null neurons is not a default outcome of inappropriate S-phase entry.
-
RB can be inactivated by phosphorylation and degradation.
-
RB degradation is required for tumour necrosis factor type I receptor-induced apoptosis.
-
Most sporadic human cancers inactivate RB function by exploiting pathways that regulate RB phosphorylation.
-
Loss of RB can only contribute to tumour development under conditions in which apoptosis response is compromised.
Abstract
Recent studies have shown that RB can inhibit apoptosis, independently of its ability to block cell proliferation. This poses the question of how cells choose to grow or to die when RB becomes inactivated. RB is phosphorylated following mitogenic stimulation, but it is degraded in response to death stimuli. Most sporadic cancers also inactivate RB by phosphorylation, rather than losing RB entirely — possibly to exploit the survival advantage conferred by RB under stress. Drawing from the different mechanisms of RB inactivation, we propose two models for ways in which cells use RB to make the choice of life versus death.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
£139.00 per year
only £11.58 per issue
Buy this article
- Purchase on SpringerLink
- 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
Nevins, J. R. The Rb/E2F pathway and cancer. Hum. Mol. Genet. 10, 699–703 (2001).
Harbour, J. W. & Dean, D. C. Rb function in cell-cycle regulation and apoptosis. Nature Cell Biol. 2, E65–E67 (2000).
Nielsen, S. J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565 (2001).
Clarke, A. R. et al. Requirement for a functional Rb-1 gene in murine development. Nature 359, 328–330 (1992).
Jacks, T. et al. Effects of an Rb mutation in the mouse. Nature 359, 295–300 (1992).
Lee, E. Y. et al. Mice deficient for Rb are nonviable and show defects in neurogenesis and haematopoiesis. Nature 359, 288–294 (1992).
Morgenbesser, S. D., Williams, B. O., Jacks, T. & DePinho, R. A. p53-dependent apoptosis produced by Rb-deficiency in the developing mouse lens. Nature 371, 72–74 (1994).
Macleod, K. F., Hu, Y. & Jacks, T. Loss of Rb activates both p53-dependent and independent cell death pathways in the developing mouse nervous system. EMBO J. 15, 6178–6188 (1996).
Tsai, K. Y. et al. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol. Cell 2, 293–304 (1998).
Saavedra, H. I. et al. Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb. Cell Growth Differ. 13, 215–225 (2002).
Wang, X. The expanding role of mitochondria in apoptosis. Genes Dev. 15, 2922–2933 (2001).
Moroni, M. C. et al. Apaf-1 is a transcriptional target for E2F and p53. Nature Cell Biol. 3, 552–558 (2001). This study identified E2F and p53 binding sites in the Aapf1 promoter. It was shown that Apaf1 mRNA and protein were inappropriately upregulated in the Rb-null embryos.
Fortin, A. et al. APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. J. Cell Biol. 155, 207–216 (2001). By infecting Apaf1-null and wild-type neurons with an adenoviral vector that expresses 53, this study showed that Apaf1 is required for p53 to induce apoptosis in vivo.
Guo, Z., Yikang, S., Yoshida, H., Mak, T. W. & Zacksenhaus, E. Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis. Cancer Res. 61, 8395–8400 (2001).
Ziebold, U., Reza, T., Caron, A. & Lees, J. A. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev. 15, 386–391 (2001). In this study, Rb−/− E2f3−/− embryos were examined and it was shown that E2f3-knockout mice could suppress the ectopic apoptosis phenotype of Rb-null neurons. These results indicate that the deregulation of E2f3 contributed to neuronal apoptosis in the absence of Rb.
Leone, G. et al. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol. Cell 8, 105–113 (2001). Experimenting with mouse embryonic fibroblasts from E2f1-, E2f2- and E2f3-knockout mice, this study showed that E2f1, but not E2f2 or E2f3, was required for Myc-induced apoptosis.
Simpson, M. T. et al. Caspase 3 deficiency rescues peripheral nervous system defect in retinoblastoma nullizygous mice. J. Neurosci. 21, 7089–7098 (2001).
Zheng, T. S. et al. Deficiency in caspase-9 or caspase-3 induces compensatory caspase activation. Nature Med. 6, 1241–1247 (2000).
Nahle, Z. et al. Direct coupling of the cell cycle and cell death machinery by E2F. Nature Cell Biol. 4, 859–864 (2002). Using in silico methods, this study identified E2F binding sites in the promoters of several caspase genes, including CASP3, 7, 8 and 9. When the expression of these caspases was examined during cell-cycle progression, it was found that some, but not all, of these caspases were induced as cells enter S phase.
Lasorella, A., Noseda, M., Beyna, M., Yokota, Y. & Iavarone, A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 407, 592–598 (2000).
Jiang, Z. et al. E2F1 and p53 are dispensable, whereas p21(Waf1/Cip1) cooperates with Rb to restrict endoreduplication and apoptosis during skeletal myogenesis. Dev. Biol. 227, 8–41 (2000). This study showed that, unlike the developing nervous systems, E2f1 and p53 were not required for the ectopic apoptosis phenotype of Rb-null skeletal muscle.
Iavarone, A., Garg, P., Lasorella, A., Hsu, J. & Israel, M. A. The helix–loop–helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev. 8, 1270–1284 (1994).
Zacksenhaus, E. et al. pRb controls proliferation, differentiation, and death of skeletal muscle cells and other lineages during embryogenesis. Genes Dev. 10, 3051–3064 (1996).
Wang, J., Guo, K., Wills, K. N. & Walsh, K. Rb functions to inhibit apoptosis during myocyte differentiation. Cancer Res. 57, 351–354 (1997).
Ferguson, K. L. et al. Telencephalon-specific Rb knockouts reveal enhanced neurogenesis, survival and abnormal cortical development. EMBO J. 21, 3337–3346 (2002). By examining conditional Rb-knockout mice, this study showed that ectopic apoptosis could be uncoupled from the ectopic S-phase entry in the Rb-null neurons.
MacPherson, D. et al. Conditional mutation of Rb causes cell cycle defects without apoptosis in the central nervous system. Mol. Cell. Biol. 23, 1044–1053 (2003).By experimenting with an independently derived strain of conditional Rb-knockout mice, this study reported observations similar to those in the study cited in reference 25. The authors conclude that hypoxia induced by the developmental defect of Rb-null erythrocytes contributes to the ectopic apoptosis phenotype of neurons in Rb-null embryos. So, the ectopic apoptosis phenotypes in Rb-null embryos is a non-cell-autonomous event.
Field, S. J. et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561 (1996).
Muller, H. et al. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 15, 267–285 (2001). Using inducible E2F-ER proteins combined with microarray analyses, this study found that E2Fs activated S-phase genes and genes involved in differentiation, development and apoptosis.
Chau, B. N. et al. Signal-dependent protection from apoptosis in mice expressing caspase-resistant Rb. Nature Cell Biol. 4, 757–765 (2002). Through the generation of Rb-MI knockin mice that express a caspase-resistant Rb protein, this study showed that caspase-mediated degradation of Rb is required for tumor necrosis factor receptor type I, but not DNA damage to induce apoptosis. These results indicate that Rb is an anti-apoptotic factor that regulates selective death pathways.
Tan, X. & Wang, J. Y. The caspase-RB connection in cell death. Trends Cell Biol. 8, 116–120 (1998).
Fattman, C. L., Delach, S. M., Dou, Q. P. & Johnson, D. E. Sequential two-step cleavage of the retinoblastoma protein by caspase-3/-7 during etoposide-induced apoptosis. Oncogene 20, 2918–2926 (2001).
Fattman, C. L., An, B. & Dou, Q. P. Characterization of interior cleavage of retinoblastoma protein in apoptosis. J. Cell. Biochem. 67, 399–408 (1997).
Tan, X., Martin, S. J., Green, D. R. & Wang, J. Y. Degradation of retinoblastoma protein in tumor necrosis factor- and CD95-induced cell death. J. Biol. Chem. 272, 9613–9616 (1997).
Boutillier, A. L., Trinh, E. & Loeffler, J. P. Caspase-dependent cleavage of the retinoblastoma protein is an early step in neuronal apoptosis. Oncogene 19, 2171–2178 (2000).
Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13, 2514–2526 (1999).
Tang, G., Yang, J., Minemoto, Y. & Lin, A. Blocking caspase-3-mediated proteolysis of IKKβ suppresses TNF-α-induced apoptosis. Mol. Cell 8, 1005–1016 (2001).
Morris, E. J. & Dyson, N. J. Retinoblastoma protein partners. Adv. Cancer Res. 82, 1–54 (2001).
Wang, J. Y. Regulation of cell death by the Abl tyrosine kinase. Oncogene 19, 5643–5650 (2000).
Welch, P. J. & Wang, J. Y. A C-terminal protein-binding domain in the retinoblastoma protein regulates nuclear c-Abl tyrosine kinase in the cell cycle. Cell 75, 779–790 (1993).
Shim, J. et al. Rb protein down-regulates the stress-activated signals through inhibiting c-Jun N-terminal kinase/stress-activated protein kinase. J. Biol. Chem. 275, 14107–14111 (2000).
Doostzadeh-Cizeron, J., Evans, R., Yin, S. & Goodrich, D. W. Apoptosis induced by the nuclear death domain protein p84N5 is inhibited by association with Rb protein. Mol. Biol. Cell 10, 3251–3261 (1999).
Doostzadeh-Cizeron, J., Yin, S. & Goodrich, D. W. Apoptosis induced by the nuclear death domain protein p84N5 is associated with caspase-6 and NF-κB activation. J. Biol. Chem. 275, 25336–25341 (2000).
Pennaneach, V. et al. The large subunit of replication factor C promotes cell survival after DNA damage in an LxCxE motif- and Rb-dependent manner. Mol. Cell 7, 715–727 (2001).
Schwarz, J. K. et al. Interactions of the p107 and Rb proteins with E2F during the cell proliferation response. EMBO J. 12, 1013–1020 (1993).
Barkett, M. & Gilmore, T. D. Control of apoptosis by Rel/NF-κB transcription factors. Oncogene 18, 6910–6924 (1999).
Datta, S. R., Brunet, A. & Greenberg, M. E. Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927 (1999).
Sherr, C. J. Cancer cell cycles. Science 274, 1672–1677 (1996).
Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).
Nobori, T. et al. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368, 753–756 (1994).
Merlo, A. et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nature Med. 1, 686–692 (1995).
Baylin, S. B., Herman, J. G., Graff, J. R., Vertino, P. M. & Issa, J. P. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv. Cancer Res. 72, 141–196 (1998).
Zukerberg, L. R. et al. Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod. Pathol. 8, 560–567 (1995).
Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001).
White, E. Regulation of p53-dependent apoptosis by E1A and E1B. Curr. Top. Microbiol. Immunol. 199, 34–58 (1995).
Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000). In this study, tissue-specific knockout of Rb was introduced into the Trp53-knockout background. This led to the formation of medulloblastoma in mice.
Mairal, A. et al. Detection of chromosome imbalances in retinoblastoma by parallel karyotype and CGH analyses. Genes Chromosom. Cancer 28, 370–379 (2000).
Chen, D., Gallie, B. L. & Squire, J. A. Minimal regions of chromosomal imbalance in retinoblastoma detected by comparative genomic hybridization. Cancer Genet. Cytogenet. 129, 57–63 (2001).
Lee, E. Y. et al. Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev. 8, 2008–2021 (1994).
Hu, N. et al. Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance. Oncogene 9, 1021–1027 (1994).
Robanus-Maandag, E. et al. p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev. 12, 1599–1609 (1998).
Jiang, Z. & Zacksenhaus, E. Activation of retinoblastoma protein in mammary gland leads to ductal growth suppression, precocious differentiation, and adenocarcinoma. J. Cell Biol. 156, 185–198 (2002). This study examined several lines of transgenic mice that express a phosphorylation-resistant (constitutively active) Rb in the mouse mammary epithelium. Some of these mice developed adenocarcinomas, indicating that constitutive Rb activity facilitates tumour development in vivo . This could be because the constitutively active form of Rb protects mammary epithelial cells from stress-induced apoptosis.
Harvey, M., Vogel, H., Lee, E. Y., Bradley, A. & Donehower, L. A. Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res. 55, 1146–1151 (1995).
Williams, B. O. et al. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nature Genet. 7, 480–484 (1994).
Yamasaki, L. et al. Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/−)mice. Nature Genet. 18, 360–364 (1998).
Acknowledgements
We are grateful to the Wang lab members for stimulating discussion and critical reading of the manuscript throughout its preparation. B.N.C is supported by a postdoctoral fellowship from the Damon Runyon Cancer Research Foundation. This work is supported by a National Cancer Institute grant awarded to J.Y.J.W.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chau, B., Wang, J. Coordinated regulation of life and death by RB. Nat Rev Cancer 3, 130–138 (2003). https://doi.org/10.1038/nrc993
Issue Date:
DOI: https://doi.org/10.1038/nrc993