TNF-α signaling in Fanconi anemia

Du, Wei; Erden, Ozlem; Pang, Qishen

doi:10.1016/j.bcmd.2013.06.005

Cited by 44 publications

(67 citation statements)

References 182 publications

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“…Of note, it has also been proposed that cytokines that are upregulated in FA, such as TNF-α or TGF-β, may directly harm hematopoietic stem cells or modulate DNA damage repair in the stem cell compartment (Du et al 2014, Zhang et al 2016. This line of investigation may inform the development of novel therapeutic strategies for FA.…”

Section: Therapeutic Implications Of Hr Defects In Hbocmentioning

confidence: 99%

Defects in homologous recombination repair behind the human diseases: FA and HBOC

Katsuki

Takata

2016

Endocrine-Related Cancer

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Hereditary breast and ovarian cancer (HBOC) syndrome and a rare childhood disorder Fanconi anemia (FA) are caused by homologous recombination (HR) defects, and some of the causative genes overlap. Recent studies in this field have led to the exciting development of PARP inhibitors as novel cancer therapeutics and have clarified important mechanisms underlying genome instability and tumor suppression in HR-defective disorders. In this review, we provide an overview of the basic molecular mechanisms governing HR and DNA crosslink repair, highlighting BRCA2, and the intriguing relationship between HBOC and FA.

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Section: Therapeutic Implications Of Hr Defects In Hbocmentioning

confidence: 99%

Defects in homologous recombination repair behind the human diseases: FA and HBOC

Katsuki

Takata

2016

Endocrine-Related Cancer

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“…Bone marrow failure has been reported to be associated with an increased inflammatory response, 16 and inflammatory cytokines such as TNF-a are known to be associated with inhibition of erythropoiesis. 17 Therefore, it is possible that GATA1 expression may be reduced in RPS19-deficient cells through inflammation and activation of TNF-a, which has been shown to inhibit GATA1 in TF-1 cells.…”

Section: Blood 11 December 2014 X Volume 124 Number 25 Rps19 Deficimentioning

confidence: 99%

TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors

Бибикова

Youn

Danilova

et al. 2014

Blood

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Key Points• GATA1 is downregulated in RPS19-deficient cells and zebrafish through upregulation of p53, TNF-a, and p38 MAPK.• Treatment of rps19-deficient zebrafish with the TNF-a inhibitor etanercept rescues their erythroid and developmental defects.Diamond-Blackfan anemia (DBA) is an inherited disorder characterized by defects in erythropoiesis, congenital abnormalities, and predisposition to cancer. Approximately 25% of DBA patients have a mutation in RPS19, which encodes a component of the 40S ribosomal subunit. Upregulation of p53 contributes to the pathogenesis of DBA, but the link between ribosomal protein mutations and erythropoietic defects is not well understood. We found that RPS19 deficiency in hematopoietic progenitor cells leads to decreased GATA1 expression in the erythroid progenitor population and p53-dependent upregulation of tumor necrosis factor-a (TNF-a) in nonerythroid cells. The decrease in GATA1 expression was mediated, at least in part, by activation of p38 MAPK in erythroid cells and rescued by inhibition of TNF-a or p53. The anemia phenotype in rps19-deficient zebrafish was reversed by treatment with the TNF-a inhibitor etanercept. Our data reveal that RPS19 deficiency leads to inflammation, p53-dependent increase in TNF-a, activation of p38 MAPK, and decreased GATA1 expression, suggesting a novel mechanism for the erythroid defects observed in DBA. (Blood. 2014;124(25):3791-3798)

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“…To explore the clinical significance of Salidroside in HSC maintenance in a disease model, we employed the Fanconi anemia (FA) mouse model, in which oxidative stress has been identified as a physiologic mediator of HSC loss (10,29,48). To this end, we treated Fanca -/ -or Fancc -/ -mice and their Fig.…”

Section: Salidroside Activates Parp1 Through Binding To the Wgr Domaimentioning

confidence: 99%

Binding to WGR Domain by Salidroside Activates PARP1 and Protects Hematopoietic Stem Cells from Oxidative Stress

Erden

et al. 2014

Antioxidants & Redox Signaling

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Aims: A component of the base excision repair pathway, poly(ADP-ribose) polymerase-1 (PARP1) functions in multiple cellular processes, including DNA repair and programmed cell death. We previously showed that Salidroside, a phenylpropanoid glycoside isolated from medicinal plants, prevented the loss of hematopoietic stem cells (HSCs) in native mice and rescued HSCs repopulating in transplanted recipients under oxidative stress. The aim of this study was to investigate the mechanism by which PARP1 activation by Salidroside maintains HSCs under oxidative stress. Results: We found that although there were no spontaneous defects in hematopoiesis in Parp1 -/ -mice, oxidative stress compromised the repopulating capacity of Parp1 -/ -HSCs in transplanted recipient mice. A biochemical study using truncated proteins lacking the defined functional domains of PARP1 showed that the tryptophan-glycine-arginine-rich (WGR) domain of PARP1 was critical for Salidroside binding and subsequent PARP1 activation under oxidative stress. Functionally, complementation of Parp1 -/ -HSCs with full-length PARP1 WT , but not the PARP1 R591K mutant in WGR domain restored Salidroside-stimulated PARP1 activation in vitro. Mechanistically, activated PARP1 by Salidroside enhanced the repopulating capacity of the stressed HSCs by accelerating oxidative DNA damage repair. Innovations and Conclusion: Our findings reveal the action of mechanism for Salidroside in PARP1 stimulation and a novel role of PARP1 activation in maintaining HSC function under oxidative stress.

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TNF-α signaling in Fanconi anemia

Cited by 44 publications

References 182 publications

Defects in homologous recombination repair behind the human diseases: FA and HBOC

Defects in homologous recombination repair behind the human diseases: FA and HBOC

TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors

Binding to WGR Domain by Salidroside Activates PARP1 and Protects Hematopoietic Stem Cells from Oxidative Stress

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