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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE13408 | GEO | 2009/09/01

SECONDARY ACCESSION(S): PRJNA109767

REPOSITORIES: GEO

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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

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2014-01-01 | E-GEOD-37577 | biostudies-arrayexpress

Gene expression profile of cerebral cortical cells after Rb family inactivation in progenitors and neurons

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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

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

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 (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.

2014-04-14 | GSE54924 | GEO

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TRANSCRIPTIONAL ACTIVATION BY E2F4 INDEPENDENT OF THE RB FAMILY

Project description:E2F transcription factors are central regulators of cell cycle progression and cell fate decisions in mammalian cells. E2F4 is a transcriptional repressor implicated in cell cycle arrest and whose repressive activity depends on its interaction with members of the RB family. E2F4 often represents the predominant E2F activity in cells. Here we show that E2F4 is important for the proliferation and the survival of mouse embryonic stem cells. In these cells, E2F4 acts in part as a transcriptional activator that promotes the expression of cell cycle genes. Importantly, this role for E2F4 is completely independent of the RB family. Accordingly, an unbiased analysis of the E2F4 interactome shows that E2F4 functionally interacts with chromatin regulators associated with gene activation in RB family-mutant cells. Taken together, our findings uncover a non-canonical role for E2F4 that reveal novel insights into the biology of rapidly dividing cell types.

2019-04-26 | PXD008796 | Pride

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