Loss of Rb activates both p53‐dependent and independent cell death pathways in the developing mouse nervous system.
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Extensive apoptosis occurs in the nervous system of mouse embryos homozygous mutant for a targeted disruption of the retinoblastoma (Rb) gene. This cell death is present in both the central (CNS) and peripheral nervous systems (PNS) and is associated with abnormal S phase entry of normally post-mitotic neurons. Aberrant proliferation in the CNS correlates with increased free E2F DNA binding activity and increased expression of cyclin E, an E2F target gene and critical cell cycle regulator. Cell death in the CNS is accompanied by increased levels of the p53 tumor suppressor gene product and increased expression of the p53 target gene, p21Waf-1/Cip-1. However, induction of p53 is not observed in the PNS of Rb-mutant embryos, nor does loss of p53 function inhibit cell death in the PNS. Surprisingly, p21Waf-1/Cip-1 is induced in the sensory ganglia of Rb-mutant embryos in a p53-independent manner. Although loss of p53 gene function prevents cell death in the CNS of Rb-mutant embryos, it does not restore normal proliferative control.
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E2F1 activity mediates p53-dependent apoptosis in response to loss of RB.
“E2F1 activity is an important mediator of p53-dependent apoptosis in response to loss of RB74,75”
From Cellular mechanisms of tumour suppression by the retinoblastoma gene (2008) · cites this paper as [75]
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Ferguson, K. L., Vanderluit, J. L., Hébert, J. M., McIntosh, W. C., Tibbo, E., MacLaurin, J. G., Park, D. S., Wallace, V. A., Vooijs, M., McConnell, S. K., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf338 · Cited by 156 · see citing works
Perp Is a Mediator of p53-Dependent Apoptosis in Diverse Cell Types
Ihrie, R. A., Reczek, E., Horner, J. S., Khachatrian, L., Sage, J., Jacks, T., & Attardi, L. D. (2003) · Current Biology · doi:10.1016/j.cub.2003.10.055 · Cited by 118 · see citing works
Self-citationA Critical Temporal Requirement for the Retinoblastoma Protein Family During Neuronal Determination
Slack, R. S., El-Bizri, H., Wong, J., Belliveau, D. J., & Miller, F. D. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.140.6.1497 · Cited by 100 · see citing works
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The Rb pathway in neurogenesis
Ferguson, K. L., & Slack, R. S. (2001) · Neuroreport · doi:10.1097/00001756-200107030-00001 · Cited by 57 · see citing works
Jiang, Z., & Zacksenhaus, E. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200106084 · Cited by 55 · see citing works
Caspase 3 Deficiency Rescues Peripheral Nervous System Defect in Retinoblastoma Nullizygous Mice
Simpson, M. T. W., MacLaurin, J. G., Xu, D., Ferguson, K. L., Vanderluit, J. L., Davoli, M. A., Roy, S., Nicholson, D. W., Robertson, G. S., Park, D. S., et al. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-18-07089.2001 · Cited by 35 · see citing works
Reduction of apoptosis in Rb-deficient embryos via Abl knockout
Borges, H. L., Hunton, I. C., & Wang, J. Y. J. (2007) · Oncogene · doi:10.1038/sj.onc.1210157 · Cited by 14 · see citing works
- Authors
- Macleod, K. F., Hu, Y., & Jacks, T.
- Affiliations
- Massachusetts Institute of Technology (US)
- Venue
- The EMBO Journal
- Published
- 1996-11-01
- Volume
- 15
- Issue
- 22
- Pages
- 6178-6188
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC452439
- OpenAlex
- W1609607086
- Cited by
- 321
- References
- 83
- Citations by year
- 2023: 3 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 5
- FWCI
- 11.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- retinoblastoma gene, Rb loss, p53, apoptosis, neuronal cell death, brain development, E2F transcription factors, cyclin E, sensory ganglia, central nervous system, peripheral nervous system, postmitotic neurons, cell cycle re-entry, neuronal proliferation
- MeSH terms
- Animals, Brain, Central Nervous System, DNA-Binding Proteins, Embryonic and Fetal Development, Histocytochemistry, Immunohistochemistry, Mice, Transgenic, Mutation, Transcription Factors, Blotting, Western, Genes, p53, Genes, Retinoblastoma, S Phase, Cyclins, Proto-Oncogene Proteins p21(ras), Apoptosis, Peripheral Nervous System, Gene Expression Regulation, Developmental, Mice
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