Master or slave: The complex relationship of RBP2 and pRb

Gutierrez, Gabriel M.; Kong, Elizabeth; Hinds, Philip W.

doi:10.1016/j.ccr.2005.05.021

Cited by 11 publications

(9 citation statements)

References 12 publications

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“…KDM5 KD in BAT-LgT cells, which is a SV40 large-T antigen-immortalized brown preadipocyte model, reduced both the ability of these cells to proliferate and to accumulate lipids in response differentiation inducers. Some previous studies have reported a similar pro-proliferative role of the KDM5s (12–14,17,18), whereas the KDM5s in other cellular systems have been reported to be anti-proliferative (21,22,34,90,91). The very different cellular contexts of the studies, including malignant cell models, are likely responsible for the different functions assigned to the KDM5s.…”

Section: Discussionmentioning

confidence: 68%

The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation

Brier

Loft

Madsen

et al. 2016

Nucleic Acids Research

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The KDM5 family of histone demethylases removes the H3K4 tri-methylation (H3K4me3) mark frequently found at promoter regions of actively transcribed genes and is therefore generally considered to contribute to corepression. In this study, we show that knockdown (KD) of all expressed members of the KDM5 family in white and brown preadipocytes leads to deregulated gene expression and blocks differentiation to mature adipocytes. KDM5 KD leads to a considerable increase in H3K4me3 at promoter regions; however, these changes in H3K4me3 have a limited effect on gene expression per se. By contrast, genome-wide analyses demonstrate that KDM5A is strongly enriched at KDM5-activated promoters, which generally have high levels of H3K4me3 and are associated with highly expressed genes. We show that KDM5-activated genes include a large set of cell cycle regulators and that the KDM5s are necessary for mitotic clonal expansion in 3T3-L1 cells, indicating that KDM5 KD may interfere with differentiation in part by impairing proliferation. Notably, the demethylase activity of KDM5A is required for activation of at least a subset of pro-proliferative cell cycle genes. In conclusion, the KDM5 family acts as dual modulators of gene expression in preadipocytes and is required for early stage differentiation and activation of pro-proliferative cell cycle genes.

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Section: Discussionmentioning

confidence: 68%

The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation

Brier

Loft

Madsen

et al. 2016

Nucleic Acids Research

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“…Displacement of BRM is dependent on p300 and provides the opportunity for pRB-dependent recruitment of the activating SWI/SNF complex containing BRG1. BRG1, like KDM5A, contains a canonical pRB-binding motif, LxCxE, and can partner directly with pRB (13, 20). BRG1-specific SWI/SNF is required in all tissue types for activation of key tissue-specific genes, and is essential for the ultimate recruitment of RNA polymerase-II to enact transcription on Alpl .…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Activation by pRB and Its Coordination with SWI/SNF Recruitment

2010

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A central question in cancer biology is why most tumor susceptibility genes are linked with only limited types of cancer. Human germ-line mutation of the retinoblastoma susceptibility gene Rb1 is closely linked with just retinoblastoma and osteosarcoma, although the gene is universally expressed. Functional analysis of pRB and its close relatives, p107 and p130, has largely focused on their roles in repression of proliferation across all tissue types, but genetic evidence indicates an active requirement for pRB in osteoblast differentiation that correlates more directly with osteosarcoma susceptibility. Still, potential promoter targets of pRB and its role in normally differentiating osteoblasts remain insufficiently characterized. Here, an early marker of osteoblast differentiation, alkaline phosphatase, is identified as a direct promoter activation target of pRB. One role of pRB on this promoter is to displace the histone lysine demethylase KDM5A, thereby favoring trimethylation of H3K4, a promoter activation mark. A major new aspect of pRB-mediated transcriptional activation revealed in this promoter analysis is its role in recruitment of an activating SWI/SNF chromatin-remodeling complex. SWI/SNF is a critical coordinator of tissue-specific gene expression. In osteoblasts, SWI/SNF complexes containing the BRM ATPase repress osteoblast-specific genes to maintain the precursor state, whereas the alternative ATPase BRG1 distinguishes an activating SWI/SNF complex necessary for RNA polymerase-II recruitment. A switch from BRM to BRG1 on the alkaline phosphatase promoter marks the onset of differentiation and is accomplished in a precise two-step mechanism. Dissociation of BRM-containing SWI/SNF depends on p300, and association of BRG1-containing SWI/SNF depends on pRB. Cancer Res; 70(21); 8282-7. ©2010 AACR.

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“…8A). When a cell commits to a cell lineage, it downregulates KDM5b expression, possibly by KDM5a, which has been shown to oppose KDM5b function in cell cycle regulation (16). In a developmental context, this would be intertwined with control over the recruitment of KDM5b in response to signal cascades (Fig.…”

Section: While Mescsmentioning

confidence: 99%

The Histone Demethylase KDM5b/JARID1b Plays a Role in Cell Fate Decisions by Blocking Terminal Differentiation

Dey

Stalker

Schnerch

et al. 2008

Molecular and Cellular Biology

116

111

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The histone demethylase lysine demethylase 5b (KDM5b) specifically demethylates lysine 4 of histone H3 (meH3K4), thereby repressing gene transcription. KDM5b regulates cell cycle control genes in cancer and is expressed in the early epiblast. This suggests that KDM5b plays a developmental role by maintaining uncommitted progenitors. Here we show that transient overexpression of KDM5b in embryonic stem cells decreases the expression of at least three different modulators of cell fate decisions, Egr1, p27 KIP1 , and BMI1, by demethylation of their promoters. Constitutively increased KDM5b expression results in an increased mitotic rate and a decreased global 3meH3K4 but no change in cell identity. Results of two separate differentiation assays, neural differentiation and embryoid body EB (EB) formation, showed that KDM5b reduced the terminally differentiated cells and increased proliferating progenitors. These were achieved by two mechanisms, blocking of the upregulation of cell lineage markers and maintenance of cyclins, that allowed cells to escape differentiation and remain uncommitted. Additionally, EBs maintain high levels of Oct4 and Nanog and can be dissociated to reestablish highly proliferative cultures. The persistence of uncommitted progenitors may be due to the direct regulation of the Tcf/Lef family member mTcf3/hTcf7L1, an upstream regulator of Nanog expression. These findings demonstrate a role for KDM5b in the choice between proliferation and differentiation during development.Transcriptional control is a dynamic process, during which several different histone residues are modified to change RNA polymerase's ability to access the transcriptional start site (19,42). A key component in this process is the methylation of histone H3 lysine 4 (H3K4). Methylation of H3K4 is a key regulator of RNA polymerase binding to active genes (41) and of transcription factor binding within promoter elements (43). The ability of this epigenetic mark to control multiple points in transcription suggests that modulation of H3K4 methylation plays a role in both the activation and the repression of genes.A key aspect of H3K4 methylation is how this epigenetic mark is removed, thereby reducing RNA polymerase's localization to the specific genes. This loss of methyl H3K4

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Master or slave: The complex relationship of RBP2 and pRb

Cited by 11 publications

References 12 publications

The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation

The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation

Transcriptional Activation by pRB and Its Coordination with SWI/SNF Recruitment

The Histone Demethylase KDM5b/JARID1b Plays a Role in Cell Fate Decisions by Blocking Terminal Differentiation

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