RB's original CIN?: Figure 1.

Abstract

The retinoblastoma tumor suppressor RB is the downstream mediator of a cellular pathway that is thought to prevent cancer by controlling the ability of cells to enter or exit the cell cycle in G0/G1. Recently, however, accumulating evidence has suggested that RB, its family members p107 and p130, and their partners, the E2F family of transcription factors, may have important cellular functions beyond the G1/S transition of the cell cycle, including during DNA replication and at the transition into mitosis. In this issue of Genes & Development, three studies demonstrate a critical role for RB in proper chromosome condensation, centromeric function, and chromosome stability in mammalian cells, and link these cellular functions of RB to tumor suppression in mice. Here we discuss how transcriptional and posttranscriptional mechanisms under the control of the RB pathway ensure accurate progression through mitosis, thereby preventing cancer development.The RB tumor suppressor was first identified in familial cases of retinoblastoma, a pediatric cancer of the eye. RB was then found to be mutated in a large number of human tumors, including osteosarcoma; small-cell lung carcinoma; and breast, bladder, or prostate cancers. When RB itself is not mutated in human cancer cells, these cells nearly always carry alterations in upstream regulators of RB function, such as the p16 Ink4a cell cycle inhibitor or the CyclinD/Cdk4,6 kinase complexes. A vast number of experiments have assigned a potent role for the RB pathway at the G1/S transition of the cell cycle, and provide a model to explain why loss of RB function may lead to cancer: In G0/G1, RB is mostly hypophosphorylated, and is able to bind and control the expression of critical cell cycle genes by interacting with E2F transcription factors and chromatin remodeling complexes; as cells enter the cell cycle, RB becomes inactivated by phosphorylation, allowing E2F to transactivate the expression of genes essential for DNA replication and cell cycle progression. RB inactivation in cancer cells by direct mutation or constitutive hyperphosphorylation leads to loss of an important checkpoint at the G1/S transition of their cell cycle, and mutant cells proliferate even under cytostatic conditions. This model explains why the RB pathway is such a strong tumor suppressor pathway, but it does not exclude that RB has other tumor suppressor activities; for instance, RB may also directly promote differentiation, which could play a role in inhibiting cancer development (for review, see Burkhart and Sage 2008). Loss of RB function and chromosomal instability (CIN)Human tumor cells often show signs of genomic instability (Negrini et al. 2010). Accumulating evidence has indicated that loss of RB function may play a role in this process; for example, by inducing defects during the replication of DNA, and potentially by causing abnormal segregation of chromosomes during mitosis (Kennedy et al. 2000;Foijer et al. 2005;Eguchi et al. 2007). Embryonic stem cells (ESCs), which are largely devoid o...

Cortical excitatory neurons become protected from cell division during neurogenesis in an Rb family-dependent manner

“…Rb is a transcriptional repressor of the E2F-target genes important for G1/S transition but also controls the G2/M transition by direct transcriptional regulations and epigenetic regulations (Sage and Straight, 2010). For example, the E2F-target gene MAD2L1 encoding the mitotic checkpoint protein MAD2 is downregulated in Rb-deficient MEFs, which leads to genomic instability (Hernando et al, 2004).…”

ATM Mediates pRB Function To Control DNMT1 Protein Stability and DNA Methylation

“…pRB inactivation induces DNA double-strand breaks (DSBs) via multiple pathways (12)(13)(14)(15)(16)(17). The MRN (Mre11, Rad50, and NBS1) sensor complex detects DSBs, rapidly activates ataxia telangiectasia mutated (ATM), and recruits ATM to the site of DSBs.…”

Designing a broad-spectrum integrative approach for cancer prevention and treatment

“…In many cases, the loss of RB is due to defects in upstream signaling molecules such as inactivation of INK4. Loss of p16ink4a results in unopposed activation of CDK4/6, which phosphorylates the RB protein thereby activating E2F-mediated transcription of genes involved in entry into the cell cycle [94]. …”