Dataset Information

TRANSCRIPTIONAL ACTIVATION BY E2F4 INDEPENDENT OF THE RB FAMILY

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Embryo, Retinal Pigment Epithelial Cell, Embryonic Stem Cell, Retinal Pigment Epithelium Cell

SUBMITTER: Janos Demeter

LAB HEAD: Julien Sage

PROVIDER: PXD008796 | Pride | 2019-04-26

REPOSITORIES: Pride

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Publications

E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family.

Hsu Jenny J Arand Julia J Chaikovsky Andrea A Mooney Nancie A NA Demeter Janos J Brison Caileen M CM Oliverio Romane R Vogel Hannes H Rubin Seth M SM Jackson Peter K PK Sage Julien J

Nature communications 20190703 1

E2F transcription factors are central regulators of cell division and cell fate decisions. E2F4 often represents the predominant E2F activity in 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. 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 exp ...[more]

PMID: 31270324

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Project description:ARHGAP36 is an atypical Rho GTPase-activating protein (GAP) family member that drives both spinal cord development and tumorigenesis, acting in part through an N-terminal motif that suppresses protein kinase A and activates Gli transcription factors. ARHGAP36 also contains isoform-specific N-terminal sequences, a central GAP-like module, and a unique C-terminal domain, and the functions of these regions remain unknown. Here we have mapped the ARHGAP36 structure-activity landscape using a deep sequencing-based mutagenesis screen and truncation mutant analyses. Using this approach, we have discovered several residues in the GAP homology domain that are essential for Gli activation and a role for the C-terminal domain in counteracting an N-terminal autoinhibitory motif that is present in certain ARHGAP36 isoforms. In addition, each of these sites modulates ARHGAP36 recruitment to the plasma membrane or primary cilium. Through comparative proteomics, we also have identified proteins that preferentially interact with active ARHGAP36, and we demonstrate that one binding partner, prolyl oligopeptidase-like protein, is a novel ARHGAP36 antagonist. Our work reveals multiple modes of ARHGAP36 regulation and establishes an experimental framework that can be applied towards other signaling proteins. This accession contains raw data from an interactome analysis of wild-type and L317P mutant ARHGAP36 isoform 2, represented in Fig. 5 and Dataset S2 of the associated publication.nactive GAP-like domain mutant, we have also identified prolyl oligopeptidase-like protein (PREPL) as a direct antagonist that decreases ARHGAP36 protein expression. In combination, our systems-level analyses uncover an ensemble of mechanisms that regulate ARHGAP36 expression, localization, and activity state, providing a potential means for context-specific ARHGAP36 functions. This accession contains raw data from an interactome analysis of wild-type and L317P mutant ARHGAP36 isoform 2, represented in Fig. 5 and Dataset S2 of the associated publication.

Dataset Information

TRANSCRIPTIONAL ACTIVATION BY E2F4 INDEPENDENT OF THE RB FAMILY

Publications

E2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family.

Similar Datasets

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