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A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene targeted mice

ABSTRACT: The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1∆G) are defective in regulating E2F target genes. Surprisingly, cell cycle regulation in Rb1∆G/∆G MEFs strongly resembles that of wild type. In a serum deprivation induced cell cycle exit, Rb1∆G/∆G MEFs display a similar magnitude of E2F target gene derepression as Rb1-/-, even though Rb1∆G/∆G cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1∆G/∆G MEFs is responsive to p16 expression, indicating that the ΔG-pRB protein can be activated in G1 to arrest proliferation through non-E2F mechanisms. Some Rb1∆G/∆G mice die neonatally with a muscle degeneration phenotype, while the others live a normal lifespan with no evidence of spontaneous tumor formation. Histological analysis reveals discrete examples of hyperplasia in the mammary epithelium, but most tissues appear normal while being accompanied by derepression of pRB regulated E2F targets. This suggests that non-E2F, pRB dependent pathways may have a more relevant role in proliferative control than previously identified.

ORGANISM(S): Mus musculus

PROVIDER: GSE54924 | GEO | 2014/04/14

SECONDARY ACCESSION(S): PRJNA238041

REPOSITORIES: GEO

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A retinoblastoma allele that is mutated at its common E2F interaction site inhibits cell proliferation in gene targeted mice

Project description:The retinoblastoma protein (pRB) is best known for regulating cell proliferation through E2F transcription factors. In this report we investigate the properties of a targeted mutation that disrupts pRB interactions with the transactivation domain of E2Fs. Mice that carry this mutation endogenously (Rb1DeltaG) are defective in regulating E2F target genes. Surprisingly, cell cycle regulation in Rb1DeltaG/DeltaG MEFs strongly resembles that of wild type. In a serum deprivation induced cell cycle exit, Rb1DeltaG/DeltaG MEFs display a similar magnitude of E2F target gene derepression as Rb1-/-, even though Rb1DeltaG/DeltaG cells exit the cell cycle normally. Interestingly, cell cycle arrest in Rb1DeltaG/DeltaG MEFs is responsive to p16 expression, indicating that the DeltaG-pRB protein can be activated in G1 to arrest proliferation through non-E2F mechanisms. Some Rb1DeltaG/DeltaG mice die neonatally with a muscle degeneration phenotype, while the others live a normal lifespan with no evidence of spontaneous tumor formation. Histological analysis reveals discrete examples of hyperplasia in the mammary epithelium, but most tissues appear normal while being accompanied by derepression of pRB regulated E2F targets. This suggests that non-E2F, pRB dependent pathways may have a more relevant role in proliferative control than previously identified. Total RNA was extracted from littermate paired WT, DeltaG and null MEFs induced to enter quiencense by Serum deprivation. Expresssion levels were analyzed by Affymetrix GeneChip Mouse Gene 1.0ST Array. Relative expression was determined by BRB-Array Tools software to generate RMA values.

2014-04-14 | E-GEOD-54924 | biostudies-arrayexpress

Expression data from Pou4f3-Rb1 cKO and control inner ear

Project description:Retinoblastoma gene (Rb1) is required for proper cell cycle exit in the developing mouse inner ear and its deletion in the embryo leads to proliferation of sensory progenitor cells that differentiate into hair cells and supporting cells. In the Pou4f3-Cre:Rb1 flox/flox (Rb1 cKO) inner ear, utricular hair cells differentiate and survive into adulthood whereas differentiation and survival of cochlear hair cells are impaired. To comprehensively survey the pRb pathway in the mammalian inner ear, we performed microarray analysis of Rb1 cKO cochlea and utricle.

2011-06-01 | GSE25732 | GEO

Expression data from Pou4f3-Rb1 cKO and control inner ear

2011-05-31 | E-GEOD-25732 | biostudies-arrayexpress

Delineating the Rb1 interactome data and its modulations during cell cycle progression.

Project description:The retinoblastoma (Rb) protein is a potent tumor suppressor which is known to negatively regulate the cell cycle as well as tumor progression. Phosphorylated Rb protein (pRb) has been demonstrated to be in-charge for the key G1 checkpoint, blocking entry into S-phase and thereby the cell growth. This study was designed to capture interacting protein partners of Rb1 as the cell cycle progresses. Rb1 expressing HEK-293 cells were cultured in light, medium and heavy SILAC labels to capture the changes in Rb1 interactome as the cell cycle progressed from G0 to G1S and then to G2 phase, respectively. This data might help in understanding the cell cycle regulatory effect of Rb1 protein and complement the available information on its interacting partners.

2017-09-14 | PXD007708 | Pride

Palbociclib interferes with origin firing in a pRb independent manner

Project description:Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, promoting needs to understand more about the mechanism of inhibitors beyond pRb. Our study demonstrates here for the first time how palbociclib impairs the origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA without any induced cell cycle arrest. Furthermore, palbociclib treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of proteins of the Pre-initiation complex (Pre-IC) on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and on its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib to target genomic instability towards pRb deficient patient

2023-07-01 | GSE180530 | GEO

Hatzimanikatis1999-Regulation of the G1-S transition of the mammalian cell cycle.

Project description:A mathematical model of regulation of the G1-S transition of the mammalian cell cycle has been formulated to organize available experimental molecular-level information in a systematic quantitative framework and to evaluate the ability of this manifestation of current knowledge to calculate correctly experimentally observed phenotypes. This model includes nine components and includes cyclin-cdk complexes, a pocket protein (pRb), a transcription factor (E2F-1), and a cyclin-cdk complex inhibitor. Simulation of the model equations yields stable oscillatory solutions corresponding to cell proliferation and asymptotically stable solutions corresponding to cell cycle arrest (quiescence). Bifurcation analysis of the system suggests changes in the intracellular concentrations of either E2F or cyclin E can activate cell proliferation and that co-overexpression of these molecules can prevent cell proliferation. Further analysis suggests that the amount of inhibitor necessary to prevent cell proliferation is independent of the concentrations of cyclin E and E2F and depends only on the equilibrium ratio between the bound and unbound forms of the inhibitor to the complex.

2020-05-07 | MODEL2005070001 | BioModels

Gene expression of E2f7/8/Rb1 triple mutant liver tumors

Project description:E2F-transcription factors activate many genes involved in cell cycle progression, DNA repair, and apoptosis. Hence, E2F-dependent transcription must be tightly regulated to prevent tumorigenesis, and therefore metazoan cells possess multiple E2F regulation mechanism. The best-known is the Retinoblastoma protein (RB), which is mutated in many cancers. Atypical E2Fs (E2F7 and -8) can repress E2F-target gene expression independently of RB and are rarely mutated in cancer. Therefore, they may act as emergency brakes in RB-mutated cells to suppress tumor growth. Currently it is unknown if and how RB and atypical E2Fs functionally interact in vivo. Here, we demonstrate that mice with liver-specific combinatorial deletion of Rb and E2f7/8 have reduced life spans compared to E2f7/8 or Rb deletion alone. This was associated with increased proliferation and enhanced malignant progression of liver tumors. Hence, atypical repressor E2Fs and RB cooperatively act as tumor suppressors in hepatocytes. We propose that the complex interactions between atypical E2Fs and RB on maintenance of genetic stability underlie this context-dependency.

2021-04-22 | GSE172508 | GEO

Transcription profiling of mouse Rb family triple knock-out (TKO) embryonic stem cells as they differentiate in vivo

Project description:The retinoblastoma cell cycle regulator pRb and the two related proteins p107 and p130 are thought to suppress cancer development both by inhibiting the G1/S transition of the cell cycle in response to growth-arrest signals and by promoting cellular differentiation. Here, we investigated the phenotype of Rb family triple knock-out (TKO) embryonic stem cells as they differentiate in vivo and in culture. Confirming the central role of the Rb gene family in cell cycle progression, TKO mouse embryos did not survive past mid-gestation and differentiating TKO cells displayed increased proliferation and cell death. However, patterning and cell fate determination were largely unaffected in these TKO embryos. Furthermore, a number of TKO cells, including in the neural lineage, were able to exit the cell cycle in G1 and terminally differentiate. This ability of Rb family TKO cells to undergo cell cycle arrest was associated with the repression of target genes for the E2F6 transcription factor, uncovering a pRb-independent control of the G1/S transition of the cell cycle. These results show that the Rb gene family is required for proper embryonic development but is not absolutely essential to induce G1 arrest and differentiation in certain lineages. Experiment Overall Design: Genome-wide gene expression was analyzed for wild-type and TKO ESC and EB cells. Three biological replicates were isolated for wild-type ESCs, TKO ESCs, and wild-type EBs, while five biological replicates were isolated for TKO EBs.

2009-09-12 | E-GEOD-13408 | biostudies-arrayexpress

Cell cycle exit and terminal differentiation independent of the Rb gene family during embryonic development

2009-09-01 | GSE13408 | GEO

Transcription profiling of human T98G cells during cell cycle in T98G

Project description:The mammalian Retinoblastoma (RB) family including pRB, p107, and p130 represses E2F target genes through mechanisms that are not fully understood. In D. melanogaster, RB-dependent repression is mediated in part by the multisubunit protein complex Drosophila RBF, E2F, and Myb (dREAM) that contains homologs of the C. elegans synthetic multivulva class B (synMuvB) gene products. Using an integrated approach combining proteomics, genomics, and bioinformatic analyses, we identified a p130 complex termed DP, RB-like, E2F, and MuvB (DREAM) that contains mammalian homologs of synMuvB proteins LIN-9, LIN-37, LIN-52, LIN-54, and LIN-53/RBBP4. DREAM bound to more than 800 human promoters in G0 and was required for repression of E2F target genes. In S phase, MuvB proteins dissociated from p130 and formed a distinct submodule that bound MYB. This work reveals an evolutionarily conserved multisubunit protein complex that contains p130 and E2F4, but not pRB, and mediates the repression of cell cycle-dependent genes in quiescence. Experiment Overall Design: Gene expression during the cell cycle in T98G cells. Cells were serum starved for 72 hours to induce G0 and then restimuated to enter cell cycle by serum addition. BrdU and FACS was done simultaneously to confirm their cell cycle phase.

2008-06-16 | E-GEOD-8537 | biostudies-arrayexpress

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