Hurford Jr KR, Cobrinik D, Lee HM, Dyson N.. pRB and p107/p130 are required for the regulated expression of different sets of E2F responsive genes. Genes Dev 11: 1447-1463

Department of Medicine, Boston University, Boston, Massachusetts, United States
Genes & Development (Impact Factor: 10.8). 07/1997; 11(11):1447-63. DOI: 10.1101/gad.11.11.1447
Source: PubMed

ABSTRACT The activity of the E2F transcription factor is controlled by physical association with the retinoblastoma protein (pRB) and two related proteins, p107 and p130. The pRB family members are thought to control different aspects of E2F activity, but it has been unclear what the respective functions of these proteins might be. To dissect the specific functions of pRB, p107, and p130 we have investigated how the expression of E2F-regulated genes is changed in cultures of primary cells lacking each of these family members. Whereas no changes were found in the expression of E2F-target genes in cells lacking either p107 or p130, deregulated expression of E2F targets was seen in cells lacking pRB and in cells lacking both p107 and p130. Surprisingly, the genes that were disregulated in these two settings were completely different. These findings show that pRB and p107/p130 indeed provide different functions in E2F regulation and identify target genes that are dependent on pRB family proteins for their normal expression.

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    • "Importantly, pocket proteins are differentially expressed along the cell cycle, probably reflecting specific functions for each protein during the different cell cycle phases. In general, pRb and p107 are expressed in cycling cells, while p130 is preferentially expressed in quiescent cells, but this aspect is also cell type specific (43, 47, 48). "
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    ABSTRACT: The Rb1 gene was the first bona fide tumor suppressor identified and cloned more than 25 years ago. Since then, a plethora of studies have revealed the functions of pRb and the existence of a sophisticated and strictly regulated pathway that modulates such functional roles. An emerging paradox affecting Rb1 in cancer connects the relatively low number of mutations affecting Rb1 gene in specific human tumors, compared with the widely functional inactivation of pRb in most, if not in all, human cancers. The existence of a retinoblastoma family of proteins pRb, p107, and p130 and their potential unique and overlapping functions as master regulators of cell cycle progression and transcriptional modulation by similar processes, may provide potential clues to explain such conundrum. Here, we will review the development of different genetically engineered mouse models, in particular those affecting stratified epithelia, and how they have offered new avenues to understand the roles of the Rb family members and their targets in the context of tumor development and progression.
    Frontiers in Oncology 12/2013; 3:307. DOI:10.3389/fonc.2013.00307
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    • "The expression level of p107 is high only in proliferating cells, but knockdown of p130 results in increased expression of p107, which results in the formation of a p107-DREAM complex in quiescent cells. However, p130-/-/p107-/- mouse embryonic fibroblasts lose the ability to form a functional DREAM complex and fail to repress E2F-dependent genes expression during quiescence, causing cells to re-enter the cell cycle [21]. E2F4-/-/E2F5-/- mouse embryonic fibroblasts can also re-enter the cell cycle from quiescence but fail to arrest in the G1 phase when the CDK inhibitor INK4A is overexpressed [22]. "
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    10/2013; 2(1):29. DOI:10.1186/2162-3619-2-29
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    • "Mouse embryonic fibroblasts (MEFs) were generated from E13.5 embryos using standard procedures and cultured in DMEM with 10% FBS and antibiotics [42]. Retroviral transduction with pBABE-HrasV12 was as reported by Serrano et al. [43] and viruses were packaged in Bosc-23 cells. "
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    ABSTRACT: The Retinoblastoma protein (pRB) is a key tumor suppressor that is functionally inactivated in most cancers. pRB regulates the cell division cycle and cell cycle exit through protein-protein interactions mediated by its multiple binding interfaces. The LXCXE binding cleft region of pRB mediates interactions with cellular proteins that have chromatin regulatory functions. Chromatin regulation mediated by pRB is required for a stress responsive cell cycle arrest, including oncogene induced senescence. The in vivo role of chromatin regulation by pRB during senescence, and its relevance to cancer is not clear. Using gene-targeted mice, uniquely defective for pRB mediated chromatin regulation, we investigated its role during transformation and tumor progression in response to activation of oncogenic ras. We report that the pRB(∆L) mutation confers susceptibility to escape from HrasV12 induced senescence and allows transformation in vitro, although these cells possess high levels of DNA damage. Intriguingly, LSL-Kras, Rb1 (∆L/∆L) mice show delayed lung tumor formation compared to controls. This is likely due to the increased apoptosis seen in the early hyperplastic lesions shortly following ras activation that inhibits tumor progression. Furthermore, DMBA treatment to induce sporadic ras mutations in other tissues also failed to reveal greater susceptibility to cancer in Rb1 (∆L/∆L) mice. Our data suggests that chromatin regulation by pRB can function to limit proliferation, but its loss fails to contribute to cancer susceptibility in ras driven tumor models because of elevated levels of DNA damage and apoptosis.
    PLoS ONE 08/2013; 8(8):e72236. DOI:10.1371/journal.pone.0072236 · 3.23 Impact Factor
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