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PreprintCited by 1,153Cancer-related Molecular PathwaysOcular Oncology and TreatmentsRetinal Development and Disorders

The DOI matches its Crossref record; 171 of the 179 references it cites were found in a registry or an index.

The Rb/E2F pathway: expanding roles and emerging paradigms

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Harbour, J. William, Dean, Douglas C.·2000·Genes & Development
DOI 10.1101/gad.813200
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Abstract

The retinoblastoma gene was identified over a decade ago as the first tumor suppressor. Although the gene was initially cloned as a result of its frequent mutation in the rare pediatric eye tumor, retinoblastoma (Friend et al. 1986; Fung et al. 1987; Lee et al. 1987), it is now thought to play a fundamental role in cellular regulation and is the target of tumorigenic mutations in many cell types. The retinoblastoma gene encodes a 928–amino acid phosphoprotein, Rb, which arrests cells in the G1 phase (Weinberg 1995). Rb is phosphorylated and dephosphorylated during the cell cycle; the hyperphosphorylated (inactive) form predominates in proliferating cells, whereas the hypophosphorylated (active) form is generally more abundant in quiescent or differentiating cells (Chen et al. 1989). As a demonstration its tumor suppressor activity, Rb was reintroduced into Rb-deficient tumor cells and it blocked several features of the malignant phenotype (Huang et al. 1988). Mutations affecting the retinoblastoma gene are frequently encountered, not only in retinoblastoma but also in other cancers such as osteosarcoma, small cell lung cancer, prostate cancer, and breast cancer (Friend et al. 1986; Fung et al. 1987; Harbour et al. 1988; Lee et al. 1988; T’Ang et al. 1988; Bookstein et al. 1990). Indeed, children with hereditary retinoblastoma have 30-fold increased risk of developing a second, nonocular malignancy, especially bone and soft tissue sarcomas in adolescence and cutaneous melanomas in adulthood (Eng et al. 1993; Moll et al. 1997). These second neoplasms occur almost exclusively in patients who have germ-line mutations in the retinoblastoma gene. As a further indication of its fundamental role in tumor suppression, Rb can be functionally inactivated by constitutive hyperphosphorylation in tumors that do not have mutations in the retinoblastoma gene (Sherr 1996). In addition, DNA tumor viruses express oncoproteins, such as adenovirus E1A, SV40 large tumor antigen, and human papillomavirus (HPV) E7, that bind and inactivate Rb; these proteins are required for the viruses to transform cells (DeCaprio et al. 1988; Whyte et al. 1988; Dyson et al. 1989). Rb function depends, at least in part, on interactions with the E2F family of DNA-binding transcription factors (E2F) (Chellappan et al. 1991; Dyson 1998; Nevins 1998). E2F sites are found in the promoters of many genes that are important for cell cycle progression, and Rb appears to repress transcription of these genes through its interaction with E2F (Blake and Azizkhan 1989; Thalmeier et al. 1989; Dalton 1992; Ohtani et al. 1995). Recent findings in the Rb/E2F field are clarifying how this pathway regulates the transition from G1 to S phase at the molecular level. Other emerging results show that this pathway also regulates other parts of the cell cycle and that it may even have roles beyond cell cycle control. In this article, we review the current understanding of the mechanism of action of Rb and its roles in cell cycle regulation, apoptosis, and development. We refer readers to recent reviews by Bartek et al. (1997), Dyson (1998), Lipinski and Jacks (1999), and Sherr and Roberts (1999) for additional in-depth analysis of the field and for historical perspectives.

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Metadata

Authors
Harbour, J. W., & Dean, D. C.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Dean, Douglas C.
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2000-10-01
Volume
14
Issue
19
Pages
2393-2409
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.813200
OpenAlex
W2152616419
Cited by
1,153
References
179
Citations by year
2026: 15 · 2025: 16 · 2024: 25 · 2023: 25 · 2022: 15 · 2021: 37 · 2020: 28 · 2019: 23 · 2018: 28 · 2017: 23 · 2016: 29 · 2015: 41 · 2014: 42 · 2013: 46 · 2012: 40
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed (publishedVersion)
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Ophthalmology › Ocular Oncology and Treatments
  • Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
Keywords
retinoblastoma protein, Rb/E2F pathway, E2F transcription factors, tumor suppressor, G1 cell cycle arrest, retinoblastoma protein phosphorylation, second primary malignancy, hereditary retinoblastoma, cell cycle regulation, cell proliferation, cell differentiation, cell death, cell adhesion, adhesion molecules
MeSH terms
Carrier Proteins, Cell Cycle, DNA-Binding Proteins, Gene Expression Regulation, Models, Biological, Morphogenesis, Transcription Factors, Retinoblastoma Protein, Genes, Retinoblastoma, Cell Cycle Proteins, E2F Transcription Factors, Retinoblastoma-Binding Protein 1

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