Article

RB's original CIN?

Department of Pediatrics, Stanford University, Stanford, California 94305, USA.
Genes & development (Impact Factor: 10.8). 07/2010; 24(13):1329-33. DOI: 10.1101/gad.1948010
Source: PubMed

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 post-transcriptional mechanisms under the control of the RB pathway ensure accurate progression through mitosis, thereby preventing cancer development.

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Available from: Julien Sage
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    • "Retinoblastoma (Rb) is a tumor suppressor gene playing important role in cell cycle regulation in proliferation, apoptosis, and neuron survival [37]–[41]. In proliferating cells, cyclins/CDKs could phosphorylate Rb protein, which in turn acts as a transcriptional factor and regulates its downstream gene expression for cell cycle process [42]. "
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    ABSTRACT: Berberine is one kind of isoquinoline alkaloid with anti-apoptotic effects on the neurons suffering ischemia. To address the explanation for these activities, the berberine-induced cell cycle arrest during neurons suffering ischemia/reperfusion had been studied in the present study. According to the in vitro neurons with oxygen-glucose deprivation and in vivo ICR mice with cerebral ischemia/reperfusion, it was found that berberine could protect the mRNA of retinoblastoma (Rb) from degradation through its function on the poly(A) tail. The prolonged half-life of retinoblastoma 1 (gene of Rb, RB1) mRNA level secures the protein level of retinoblastoma, which facilitates cell cycle arrest of neurons in the process of ischemia/reperfusion and subsequently avoids cells entering in the apoptotic process. The poly(A) tail of RB1 mRNA, as a newly identified target of berberine, could help people focus on the interaction between berberine and mRNA to further understand the biological activities and functions of berberine.
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    • "It was one of the first tumor suppressor genes identified and is commonly inactivated in several tumor types (Marshall, 1991). It is common for tumors with inactivating mutations in pRB to be aneuploid with an increased susceptibility to changes in DNA ploidy (Isaac et al., 2006; Mayhew et al., 2007; Srinivasan et al., 2007; Amato et al., 2009a,b), and recent reports have shown that pRB influences mitosis through a function that is independent of its role in cell cycle progression (Sage and Straight, 2010). The E2F transcription factor family proteins are downstream targets that are negatively regulated by pRB. "
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    ABSTRACT: Most solid tumors are characterized by abnormal chromosome numbers (aneuploidy) and karyotypic profiling has shown that the majority of these tumors are heterogeneous and chromosomally unstable. Chromosomal instability (CIN) is defined as persistent mis-segregation of whole chromosomes and is caused by defects during mitosis. Large-scale genome sequencing has failed to reveal frequent mutations of genes encoding proteins involved in mitosis. On the contrary, sequencing has revealed that most mutated genes in cancer fall into a limited number of core oncogenic signaling pathways that regulate the cell cycle, cell growth, and apoptosis. This led to the notion that the induction of oncogenic signaling is a separate event from the loss of mitotic fidelity, but a growing body of evidence suggests that oncogenic signaling can deregulate cell cycle progression, growth, and differentiation as well as cause CIN. These new results indicate that the induction of CIN can no longer be considered separately from the cancer-associated driver mutations. Here we review the primary causes of CIN in mitosis and discuss how the oncogenic activation of key signal transduction pathways contributes to the induction of CIN.
    Full-text · Article · Jun 2013 · Frontiers in Oncology
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    • "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). "
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    ABSTRACT: Cell cycle dysregulation leads to abnormal proliferation and cell death in a context-specific manner. Cell cycle progression driven via the Rb pathway forces neurons to undergo S-phase, resulting in cell death associated with the progression of neuronal degeneration. Nevertheless, some Rb- and Rb family (Rb, p107 and p130)-deficient differentiating neurons can proliferate and form tumors. Here, we found in mouse that differentiating cerebral cortical excitatory neurons underwent S-phase progression but not cell division after acute Rb family inactivation in differentiating neurons. However, the differentiating neurons underwent cell division and proliferated when Rb family members were inactivated in cortical progenitors. Differentiating neurons generated from RbÐ(/)Ð; p107Ð(/)Ð; p130Ð(/)Ð (Rb-TKO) progenitors, but not acutely inactivated Rb-TKO differentiating neurons, activated the DNA double-strand break (DSB) repair pathway without increasing trimethylation at lysine 20 of histone H4 (H4K20), which has a role in protection against DNA damage. The activation of the DSB repair pathway was essential for the cell division of Rb-TKO differentiating neurons. These results suggest that newly born cortical neurons from progenitors become epigenetically protected from DNA damage and cell division in an Rb family-dependent manner.
    Preview · Article · Apr 2013 · Development
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