Generation of a conditional knockout allele for mammalian Spen protein Mint/SHARP

Yabe, Daisuke; Fukuda, Hitoshi; Aoki, Masamitsu; Yamada, Shuichi; Takebayashi, Shinji; Shinkura, Reiko; Yamamoto, Norio; Honjo, Tasuku

doi:10.1002/dvg.20296

Cited by 41 publications

(38 citation statements)

References 27 publications

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“…Overexpression of GIT2 resulted in the significant dose-dependent elevation of the expression of multiple DNA repair proteins, e.g., HMGN1 (36) and RFC1 (41), as well as proteins involved in nuclear responses to cytotoxic DNA damage (NOP2 [42]) or involved in aging/neurodevelopment (SPEN [43]) (see Fig. S3a and b in the supplemental material).…”

Section: Resultsmentioning

confidence: 99%

Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair

Cai

Park

et al. 2015

Molecular and Cellular Biology

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Insults to nuclear DNA induce multiple response pathways to mitigate the deleterious effects of damage and mediate effective DNA repair. G-protein-coupled receptor kinase-interacting protein 2 (GIT2) regulates receptor internalization, focal adhesion dynamics, cell migration, and responses to oxidative stress. Here we demonstrate that GIT2 coordinates the levels of proteins in the DNA damage response (DDR). Cellular sensitivity to irradiation-induced DNA damage was highly associated with GIT2 expression levels. GIT2 is phosphorylated by ATM kinase and forms complexes with multiple DDR-associated factors in response to DNA damage. The targeting of GIT2 to DNA double-strand breaks was rapid and, in part, dependent upon the presence of H2AX, ATM, and MRE11 but was independent of MDC1 and RNF8. GIT2 likely promotes DNA repair through multiple mechanisms, including stabilization of BRCA1 in repair complexes; upregulation of repair proteins, including HMGN1 and RFC1; and regulation of poly(ADP-ribose) polymerase activity. Furthermore, GIT2-knockout mice demonstrated a greater susceptibility to DNA damage than their wild-type littermates. These results suggest that GIT2 plays an important role in MRE11/ATM/H2AX-mediated DNA damage responses.

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Section: Resultsmentioning

confidence: 99%

Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair

Cai

Park

et al. 2015

Molecular and Cellular Biology

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“…In particular, mutant mouse models lacking the components of Notch pathways (Notch2, ref. (5). These data clearly indicate that Notch2-mediated signals favor MZB fate at the branching point for the FOB versus MZB fate decision and regulate the balance between FOB and MZB development.…”

Section: Discussionmentioning

confidence: 70%

“…During B cell maturation, signals driven by cell-surface receptors and downstream transcription factors must be regulated in a coordinated fashion to maintain mature B cell homeostasis. In particular, both B cell antigen receptor (BCR) and BAFF, the B cell-activating factor belonging to the TNF family, relay crucial signals for mature B cell development and survival, while the Notch pathway regulates MZB cell development (1)(2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Inactivation of components of the Notch pathways in B cells in mice (Notch2, Rbpjκ, Maml1, Delta-like 1, Mib1, fringes, and Adam10) impedes MZB cell development in the spleen, with a concomitant increase in FOB cells (1)(2)(3)(4)(21)(22)(23). Conversely, deletion of the Mint/Sharp gene, a suppressor of Notch signaling, leads to an increase in MZB cells and reduction in FOB cells (5).…”

Section: Introductionmentioning

confidence: 99%

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The LRF transcription factor regulates mature B cell development and the germinal center response in mice

Sakurai¹,

Maeda²,

Lee³

et al. 2011

J. Clin. Invest.

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IntroductionHSCs give rise to immature B cells in the BM, which subsequently migrate to the secondary lymphoid organs, such as the LNs and spleen. The vast majority of newly formed BM B cells die at the transitional B cell stage during the following few days and fail to enter the long-lived mature B cell pool, which mainly consists of B1, follicular B (FOB), and marginal zone B (MZB) cells in the secondary lymphoid organs. During B cell maturation, signals driven by cell-surface receptors and downstream transcription factors must be regulated in a coordinated fashion to maintain mature B cell homeostasis. In particular, both B cell antigen receptor (BCR) and BAFF, the B cell-activating factor belonging to the TNF family, relay crucial signals for mature B cell development and survival, while the Notch pathway regulates MZB cell development (1-5).B cells are indispensable for humoral immunity, as they ultimately give rise to antibody-secreting plasma cells. During T celldependent (TD) antibody responses, naive B cells form germinal centers (GCs), a distinct histologic structure found in secondary lymphoid organs. Naive B cells become activated upon interaction with T cells and antigen-presenting cells and begin to rapidly proliferate and form the characteristic GC structure, in which 2 major genetic changes occur: somatic hypermutation (SHM) and class switch recombination (CSR). SHM modifies the affinity of the BCR for the cognate antigen by introducing predominantly point mutations into the variable region of Ig genes, while CSR replaces the constant regions of the Ig heavy (IgH) chain with those of other isotypes and allows the expression of antibodies that have the same antigen specificity but are different secondary IgH isotypes.

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“…Mice deficient for the murine SHARP homologue MINT die during late embryogenesis (21). Studies using fetal liver transfer and a conditional knockout approach have shown a SHARP deficiency to cause hematopoietic defects in marginal zone B-cell development and T-cell development (21,39,45).…”

mentioning

confidence: 99%

ETO, but Not Leukemogenic Fusion Protein AML1/ETO, Augments RBP-Jκ/SHARP-Mediated Repression of Notch Target Genes

Salat¹,

Liefke

Wiedenmann

et al. 2008

Molecular and Cellular Biology

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Notch is a transmembrane receptor that determines cell fates and pattern formation in all animal species. After specific ligand binding, the intracellular part of Notch is cleaved off and translocates to the nucleus, where it targets the DNA binding protein RBP-J. In the absence of Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. We and others have previously identified SHARP as one component of this complex. Here, we show that the corepressor ETO as well as the leukemogenic fusion protein AML1/ ETO directly interacts with SHARP, that ETO is part of the endogenous RBP-J-containing corepressor complex, and that ETO is found at Notch target gene promoters. In functional assays, corepressor ETO, but not AML1/ETO, augments SHARP-mediated repression in an histone deacetylase-dependent manner. Furthermore, either the knockdown of ETO or the overexpression of AML1/ETO activates Notch target genes. Therefore, we propose that AML1/ETO can disturb the normal, repressive function of ETO at Notch target genes. This activating (or derepressing) effect of AML1/ETO may contribute to its oncogenic potential in myeloid leukemia.

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Generation of a conditional knockout allele for mammalian Spen protein Mint/SHARP

Cited by 41 publications

References 27 publications

Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair

Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair

The LRF transcription factor regulates mature B cell development and the germinal center response in mice

ETO, but Not Leukemogenic Fusion Protein AML1/ETO, Augments RBP-Jκ/SHARP-Mediated Repression of Notch Target Genes

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