The Rb/E2F pathway: expanding roles and emerging paradigms.

By J. Harbour, D. Dean. Genes & Development, 2000

1,206 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology, Ophthalmology

View Paper: https://www.semanticscholar.org/paper/dd088b9fdbbfde7fd7da4f97c317053e10acb063

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Richard A. Young
2. D. Reinberg
3. K. Helin
4. Yi Zhang
5. G. Shapiro
6. B. Burgering
7. F. McCormick
8. C. Sherr

In Oncology

1. G. Shapiro
2. F. McCormick
3. K. Helin
4. J. M. Roberts
5. G. Williams
6. Richard A. Young
7. T. Jacks
8. C. Sherr

In Ophthalmology

1. G. Shapiro
2. C. Sherr
3. R. Weinberg
4. J. Campisi

Citations in the corpus

• Androgen receptor in prostate cancer. (2004, background): “Rb blocks cell cycle progression when it is not phosphorylated, however, phosphorylation of Rb by cyclindependent kinases relieves this block (188).”
• Cyclin-dependent kinase pathways as targets for cancer treatment. (2006, background): “This interaction not only blocks transcriptional activation of E2F, but also actively represses transcription by recruiting histone deacetylases to the promoters of genes required for S-phase entry.(14) During cell cycle progression, Rb is inactivated by sequential phosphorylation mediated by cyclin”
• E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. (2002, background): “An important function of E2F is the recruitment of the retinoblastoma (pRB) tumor suppressor family of proteins (“pocket” proteins); this family includes the related proteins p107 and p130 (Harbour and Dean 2000).”
• Cdks, cyclins and CKIs: roles beyond cell cycle regulation (2013, background): “Cdk4/6 and Cdk2, in association with their respective catalytic partners D- and E-type cyclins, are responsible for successively phosphorylating Rb, thereby alleviating its inhibition on E2F and allowing the activation of genes necessary for promoting S phase entry and DNA synthesis (Harbour and Dea”
• Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. (2001, background): “Targeting of Rb to the cyclin E gene occurs through the transcription factor E2F.”
• The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition (2007, background): “Rb phosphorylation disrupts its association with bound E2F family members, allowing the coordinated transcription of genes required for DNA replication (Weinberg, 1995; Harbour and Dean, 2000; Bracken et al., 2004).”
• Living with or without cyclins and cyclin-dependent kinases. (2004, background): “Cyclin E–Cdk2 also preferentially phosphorylates Rb on different sites from the cyclin D-dependent kinases, and these modifications may differentially impact on the interactions of Rb with E2Fs, histone deacetylases, and other chromatin-remodeling proteins (Harbour and Dean 2000).”
• Cell Cycle Inhibition by FoxO Forkhead Transcription Factors Involves Downregulation of Cyclin D (2002, background): “crucial for initiation of DNA replication and entry into S phase (16, 51).”
• Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization. (2000, background): “Each pRB family member is also able to inhibit cell cycle progression when ectopically expressed (Harbour and Dean 2000).”
• The cell cycle and cancer (2012, background): “In cancer cells, the pRB brakes are often defective, resulting in E2Fdependent G1 –S gene expression even in the absence of mitogens [14].”