Retinoblastoma family genes

Du, Wei; Pogoriler, Jennifer

doi:10.1038/sj.onc.1209651

Cited by 124 publications

(111 citation statements)

References 121 publications

(124 reference statements)

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“…The initial inactivation by CDK4 results in derepression of the cyclin E gene, and the consequent increase in cyclin E protein leads to the activation of CDK2, which further inactivates pRB having as a final outcome the transcription of S phase genes (recently reviewed in Sherr and Roberts, 2004;Ciemerych and Sicinski, 2005). However, the discovery of remaining members of the family, p107 and p130, revealed that G 1 -S progression had additional layers of complexity (recently reviewed in Classon and Dyson, 2001;Classon and Harlow, 2002;Du and Pogoriler, 2006).…”

Section: Introductionmentioning

confidence: 99%

Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex

2007

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Mammalian Mip/LIN-9 is a cell cycle regulatory protein that is negatively regulated by CDK4/cyclin D. It has been demonstrated that Mip/LIN-9 collaborates with B-Myb during S and G 2 /M in the induction of cyclins A and B, and CDK1. The ortholog of Mip/LIN-9 in Drosophila, Mip130, is part of a large multisubunit protein complex that includes RBF, repressor E2Fs and Myb, in what was termed the dREAM complex. A similar complex, although lacking B-Myb, was also described in Caenorhabditis elegans. Here, we demonstrate that unlike Drosophila, Mip/LIN-9 has mutually exclusive and cell cycle-phasespecific interactions with the mammalian orthologs of the dREAM complex. In G 0 /early G 1 , Mip/LIN-9 forms a complex with E2F4 and p107 or p130, while in late G 1 /S phase, it associates with B-Myb. The separation of Mip/LIN-9 from p107,p130/E2F4 is likely driven by phosphorylation of the pocket proteins by CDK4 since Mip/LIN-9 fails to interact with phosphorylated forms of p107,p130. Importantly, the repressor complex that Mip/LIN-9 forms with p107 takes functional precedence over the transcriptional activation linked to the Mip/LIN-9 and B-Myb interaction since expression of p107 blocks the activation of the cyclin B promoter triggered by B-Myb and Mip/LIN-9.

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Section: Introductionmentioning

confidence: 99%

Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex

2007

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“…Among the target substrates that cdks phosphorylate are the members of the retinoblastoma (Rb) family proteins, which play a pivotal role as negative regulators of cell cycle progression (Claudio et al, 1994;Caputi et al, 2005;Gallo and Giordano, 2005). This family includes the product of the Rb susceptibility gene, the pRb/p105 protein and the related p107 and pRb2/130 proteins (Mayol et al, 1993;Du and Pogoriler, 2006;Merola et al, 2006). They share the ability to recruit chromatin-remodeling enzymes and their best characterized targets are the members of the E2F/DP family of transcription factors, generally referred to as E2F (Cinti et al, 2005;Tosi et al, 2005;Genovese et al, 2006;Macaluso et al, 2006;Purev et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

et al. 2006

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One strategy in the development of anticancer therapeutics has been to arrest malignant proliferation through inhibition of the enzymatic activity of cyclin-dependent kinases (cdks), which are key regulatory molecules of the cell cycle. Over the past few years, numerous compounds with remarkable cdk inhibitory activity have been studied in cancer therapy, although it is very difficult to point out the best cdk to target. An excellent candidate appears to be cdk2, whose alteration is a pathogenic hallmark of tumorigenesis. The small molecule described in our study showed an inhibitory effect on the kinase activity of cdk2, a significant growth arrest observed in a colony formation assay and a reduction in the size of the tumor in nude mice, thus suggesting its potential role as a promising new type of mechanism-based antitumor drug, also for the treatment of hyperproliferative disorders.

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“…A major target of CycE-Cdk2 activity in promoting the G1-S phase transition is the Retinoblastoma protein (Rb), phosphorylation of which triggers the release of E2F/DP transcriptional activators and induction of many genes encoding S-phase functions, including cycE (22,29,30). Null alleles of E2F1 do not support normal cell proliferation (31).…”

Section: Cyce Wx and Designed Cyce Variants Are Deficient For Cyce-cdmentioning

confidence: 99%

Cyclin E-dependent protein kinase activity regulates niche retention of Drosophila ovarian follicle stem cells

Wang

Kalderon

2009

Proc. Natl. Acad. Sci. U.S.A.

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Whether stem cells have unique cell cycle machineries and how they integrate with niche interactions remains largely unknown. We identified a hypomorphic cyclin E allele WX that strongly impairs the maintenance of follicle stem cells (FSCs) in the Drosophila ovary but does not reduce follicle cell proliferation or germline stem cell maintenance. CycE WX protein can still bind to the cyclin-dependent kinase catalytic subunit Cdk2, but forms complexes with reduced protein kinase activity measured in vitro. By creating additional CycE variants with different degrees of kinase dysfunction and expressing these and CycE WX at different levels, we found that higher CycE-Cdk2 kinase activity is required for FSC maintenance than to support follicle cell proliferation. Surprisingly, cycE WX FSCs were lost from their niches rather than arresting proliferation. Furthermore, FSC function was substantially restored by expressing either excess DE-cadherin or excess E2F1/DP, the transcription factor normally activated by CycE-Cdk2 phosphorylation of retinoblastoma proteins. These results suggest that FSC maintenance through niche adhesion is regulated by inputs that normally control S phase entry, possibly as a quality control mechanism to ensure adequate stem cell proliferation. We speculate that a positive connection between central regulators of the cell cycle and niche retention may be a common feature of highly proliferative stem cells.cell cycle ͉ niche adhesion ͉ stem cell longevity T he ovary of Drosophila melanogaster provides an attractive model for studying stem cells because germline and somatic stem cells have well-defined locations and their behavior can be studied after directed genetic manipulations of single cell lineages (1, 2). Drosophila females have a pair of ovaries that are composed of 15-18 tube-like structures called ovarioles. Each ovariole produces eggs through an assembly line process. At the anterior tip of each ovariole is the germarium (Fig. 1A). Nonproliferating somatic cells, known as terminal filament and cap cells, reside at the anterior end of the germarium in contact with two to three germline stem cells (GSCs). A GSC divides asymmetrically to produce a new stem cell and a cystoblast, which divides four more times with incomplete cytokenesis to generate a cyst of 16 germline cells (1). Starting in region 2b (Fig. 1 A), each cyst is enveloped by a monolayer of follicle cells and is then separated from the next cyst by a short stalk as it buds from region 3 to form an egg chamber, which then progresses down the ovariole, increasing in size and maturity, and becomes an egg.The follicle cells and stalk cells are derived from the follicle stem cells (FSCs) (Fig. 1 A). Two FSC niches exist within each ovariole at the 2a/2b border region of the germarium (3). FSCs self-renew and produce ''prefollicle cell'' daughters, most of which proliferate for about eight cycles until reaching stage 6, before three cycles of endoreplication and overt differentiation (4-6). A wild-type, genetically marked FSC g...

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Retinoblastoma family genes

Cited by 124 publications

References 121 publications

Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex

Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex

A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo

Cyclin E-dependent protein kinase activity regulates niche retention of Drosophila ovarian follicle stem cells

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