Impaired Type I IFN-Induced Jak/STAT Signaling in FA-C Cells and Abnormal CD4+ Th Cell Subsets in <i>Fancc</i>−/− Mice

Fagerlie, Sara R.; Koretsky, Tara; Torok‐Storb, Beverly; Bagby, Grover C.

doi:10.4049/jimmunol.173.6.3863

Cited by 24 publications

(18 citation statements)

References 76 publications

(62 reference statements)

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“…67 Some functions of FANCC outside of the FA core complex, such as involvement in Jak/STAT signaling and apoptotic signaling, have been also proposed. 68 The gene for FA-D1 subtype, FANCD1, is identical to a breast/ovarian cancer susceptibility gene, BRCA2. 13 Carriers of monoallelic germ line mutation of BRCA2 have breast/ovarian cancer susceptibility, but patients with biallelic germ line mutations develop FA-D1 subtype of FA.…”

Section: Complementation Groups and Fa Genes And Proteinsmentioning

confidence: 99%

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Molecular pathogenesis of Fanconi anemia: recent progress

Taniguchi

D’Andrea

2006

Blood

332

311

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A rare genetic disease, Fanconi anemia (FA), now attracts broader attention from cancer biologists and basic researchers in the DNA repair and ubiquitin biology fields as well as from hematologists. FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents. Identification of 11 genes for FA has led to progress in the molecular understanding of this disease. IntroductionMany hematologists are familiar with Fanconi anemia (FA) as a cause of childhood-onset aplastic anemia. However, this rare genetic disease now attracts broader attention from cancer biologists and basic researchers. FA is a rare chromosome instability syndrome characterized by aplastic anemia, cancer and leukemia susceptibility, and cellular hypersensitivity to interstrand DNA crosslinking agents, such as cisplatin, mitomycin C (MMC), diepoxybutane (DEB), and melphalan. [1][2][3] Treatment with these agents causes increased chromosome breakage in cells derived from patients with FA. 4 Because of this hypersensitivity to DNA crosslinking agents, many researchers have speculated that the primary defect of FA cells is in DNA damage response or DNA repair, although until recently direct evidence of a connection between FA and DNA repair had not been shown.Recent identification of the responsible genes for FA has changed our view of the molecular pathogenesis of the disease. FA can be divided into at least 12 complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, and M) defined by cell fusion studies, and 11 of the 12 responsible FA genes have been identified (Table 1; Figure 1). [5][6][7][8] Proteins encoded by FA genes (FA proteins) include a ubiquitin ligase (FANCL/PHF9/ POG), 9 a monoubiquitinated protein (FANCD2), 10,11 a helicase (FANCJ/ BACH1/BRIP1), 7,8,12 a protein with helicase motifs and a nuclease motif (FANCM), and a well-known breast/ovarian cancer susceptibility protein (FANCD1/BRCA2). 13 FA proteins (including BRCA2) and another well-known breast/ovarian cancer susceptibility protein, BRCA1, cooperate in a common DNA repair process that is required for cellular resistance to DNA interstrand crosslinks (ICLs), and a concept of the Fanconi anemia-BRCA pathway 14 (or FA-BRCA network 15 ) has been proposed. Furthermore, molecular and functional interaction of FA proteins with proteins [ATM (ataxia-telangiectasia mutated), 16 MRE11, 17 BLM, [18][19][20]17,21 and ATR (ATM and Rad3-related) 22,23 ] responsible for other rare genetic chromosome instability syndromes [ataxia telangiectasia, 24 AT-like disorder, 25 Bloom syndrome, 26 Nijmegen breakage syndrome (NBS), 27 and Seckel syndrome, respectively] in DNA damage response is now evident. Therefore, the FA pathway appears to regulate DNA repair.Ubiquitination is a posttranslational modification in which a 76-residue small protein, ubiquitin, is covalently attached to a target protein (reviewed in Mani and Gelmann 28 ). Polyubiquitination is well known for its funct...

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Section: Complementation Groups and Fa Genes And Proteinsmentioning

confidence: 99%

“…127 FANCC has also been implicated in JAK/STAT signaling and apoptotic signaling. 68,[128][129][130][131][132] These functions of FA proteins, which appear to fall outside of DNA repair, are reviewed elsewhere 133 and are beyond the scope of this article.…”

Section: Function Of Fa Proteins In Intra-s Phase Cell-cycle Checkpointsmentioning

confidence: 99%

Molecular pathogenesis of Fanconi anemia: recent progress

Taniguchi

D’Andrea

2006

Blood

332

311

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“…This result indicates that an impairment of CSR occurs before initiating the DNA recombination process. A possible explanation for the impairment of germline IgG2a mRNA expression could be related to the deficiency in IFN-γ signaling that has been previously reported for Fancc deficiency (13, 14). In fact, the downstream effector of IFN-γ signaling T-bet and a proper activation of Stat1 are required for an efficient IgG2a germline mRNA expression (42, 43).…”

Section: Discussionmentioning

confidence: 75%

“…Aside DNA repair, other specific functions have been described for some FA proteins. For example, FANCC is able to interact with HSP70 to inhibit TNF-α induced apoptosis (11, 12), with STAT-1 to allow a normal IFN-γ response (13, 14) and with CtBP1 and β-catenin to modulate the WNT signaling pathway (15, 16). …”

Section: Introductionmentioning

confidence: 99%

Loss of Fancc Impairs Antibody-Secreting Cell Differentiation in Mice through Deregulating the Wnt Signaling Pathway

Sertorio

Amarachintha

Wilson

et al. 2016

The Journal of Immunology

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Fanconi anemia (FA) is characterized by a progressive bone marrow failure and an increased incidence of cancer. FA patients have high susceptibility to immune-related complications such as infection and post-transplant graft-versus-host-disease. Here we investigated the effect of FA deficiency in B cell function using the Fancc mouse model. Fancc−/− B cells show a specific defect in IgG2a switch and impaired Antibody-Secreting-Cell (ASC) differentiation. Global transcriptome analysis of naïve B cells by RNAseq demonstrates that FA deficiency deregulates a network of genes involved in immune function. Significantly, many genes implicated in Wnt signaling were aberrantly expressed in Fancc−/− B cells. Consistently, Fancc−/− B cells accumulate high levels of β-catenin under both resting and stimulated conditions, suggesting hyper-active Wnt signaling. Using an in-vivo Wnt GFP reporter assay, we verified the up-regulation of Wnt signaling as a potential mechanism responsible for the impaired Fancc−/− B cell differentiation. Further, we showed that Wnt signaling inhibits ASC differentiation possibly through repression of Blimp1 and that Fancc−/− B cells are hypersensitive to Wnt activation during ASC differentiation. Our findings identify Wnt signaling as a physiological regulator of ASC differentiation and establish a role for the Wnt pathway in normal B cell function and FA immune deficiency.

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“…IFNγ binding to IFNγ-receptor initiates the IFNγ-induced response [40] and subsequently transduces signals to activate intracytoplasmic Jak tyrosine kinase. Jak tyrosine kinase induces the activation of Stat1, preferentially activates Stat3 phosphorylation, and then translocates signals to the nucleus and induces the transcription of the target genes, contributing to the immune attack and apoptosis in bone marrow cells [41, 42]. Our results showed that DGBX treatment could decrease the expression of key molecules in the Jak/Stat signaling pathway, resulting in immunosuppressive and hematogenic functions of the AA mouse model.…”

Section: Discussionmentioning

confidence: 80%

The herbal decoction modified Danggui Buxue Tang attenuates immune-mediated bone marrow failure by regulating the differentiation of T lymphocytes in an immune-induced aplastic anemia mouse model

Deng¹,

Li²,

Wei³

et al. 2017

PLoS ONE

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Angelicae Sinensis, Radix Astragali and Rhizoma Coptidis are all herbs of modified Danggui Buxue Tang (DGBX) and are extensively applied herbs in traditional Chinese medicine for the treatment of anemia and inflammation. In this study, immune-induced AA mice were used as an animal model, and the immunosuppressive agent, Ciclosporin A (CsA), was used as a positive control. Multiple pro-inflammatory cytokines were examined by bead-based multiplex flow cytometry. The T-cell subsets were assessed using a fluorescence-activated cell sorter (FACS). Western blot analysis was used to estimate the protein expression levels of specific transcription factors for T helper cells (Th1, Th2 and Th17) and key molecules of the Janus-activated kinase (Jak)/signal transducer and activator of transcription (Stat3) signaling pathway. DGBX treatment could significantly increase the production of whole blood cells in peripheral blood (PB); inhibit the expansion of Th1 and Th17 cells; increase the differentiation of Th2 and Tregs cells; regulate the expression levels of T-bet, GATA-3, RORγ and proinflammatory cytokines; and decrease the expression levels of key molecules in the Jak/Stat signaling pathway. These results indicate that DGBX can regulate the differentiation of T lymphocytes, resulting in immunosuppressive and hematogenic functions on AA mice. DGBX might be a good candidate for inclusion in a randomized study for AA with more data on the possible side effects and doses used in humans. Ultimately, it may be used for applications of traditional medicine against AA in modern complementary and alternative immunosuppressive therapeutics.

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Impaired Type I IFN-Induced Jak/STAT Signaling in FA-C Cells and Abnormal CD4+ Th Cell Subsets in Fancc−/− Mice

Cited by 24 publications

References 76 publications

Molecular pathogenesis of Fanconi anemia: recent progress

Molecular pathogenesis of Fanconi anemia: recent progress

Loss of Fancc Impairs Antibody-Secreting Cell Differentiation in Mice through Deregulating the Wnt Signaling Pathway

The herbal decoction modified Danggui Buxue Tang attenuates immune-mediated bone marrow failure by regulating the differentiation of T lymphocytes in an immune-induced aplastic anemia mouse model

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