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Cited by 9Cytokine Signaling Pathways and InteractionsDNA Repair MechanismsBlood disorders and treatments

Stat3 and CCAAT enhancer-binding protein β (C/ebpβ) activate Fanconi C gene transcription during emergency granulopoiesis

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Shah, Chirag A., Broglie, Larisa, Hu, Liping, Bei, Ling, Huang, Weiqi, Dressler, Danielle B., Eklund, Elizabeth A.·2018·Journal of Biological Chemistry
DOI 10.1074/jbc.ra117.000528PMC PMC5857980
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Abstract

Interferon consensus sequence–binding protein (Icsbp) is required for terminating emergency granulopoiesis, an episodic event responsible for granulocyte production in response to infections and a key component of the innate immune response. Icsbp inhibits the expression of Stat3 and C/ebpβ, transcription factors essential for initiating and sustaining granulopoiesis, and activates transcription of Fanconi C ( FANCC ), a DNA repair protein. In prior studies, we noted accelerated bone marrow failure in Fancc −/− mice undergoing multiple episodes of emergency granulopoiesis, associated with apoptosis of bone marrow cells with unrepaired DNA damage. Additionally, we found increased expression of Fanconi C and F proteins during emergency granulopoiesis. These findings suggest that Icsbp protects the bone marrow from DNA damage by increasing activity of the Fanconi DNA repair pathway, but the mechanisms for FANCC activation during initiation of emergency granulopoiesis are unclear. In this study, we observed that Stat3 and C/ebpβ activate FANCC transcription and contribute to DNA repair. Our findings indicate that FancC expression is increased during Stat3- and C/ebpβ-induced initiation of emergency granulopoiesis by these transcription factors and is maintained through termination by Icsbp. Our work reveals that Stat3- and C/ebpβ-mediated FancC expression is a critical component for initiating and sustaining key innate immune responses.

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  • U-STAT3, not pY-STAT3 or pS-STAT3, transcriptionally activates Fanconi C during early phases of granulopoiesis.

    “U-STAT3 and not pY-STAT3 (or pS-STAT3) recently was found to transcriptionally activate Fanconi C, a DNA repair protein that is expressed during early phases of granulopoiesis”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Shah et al., 2018

    The Introduction says Stat3 increases FANCC transcription during initiation of emergency granulopoiesis. But the Results report equivalent FANCC promoter activation by wild-type Stat3 and mutants lacking either the tyrosine or serine phosphorylation site; the Discussion concludes that phosphorylation does not enhance activation. These passages support phosphorylation being unnecessary, not the claim that phosphorylated Stat3 does not activate FANCC. (LLM, conf=0.88)

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  1. [1]Moldovan G. L., and D'Andrea A. D. (2009) How the Fanconi anemia pathway guards the genome. Annu. Rev. Genet. 43, 223– 249 10.1146/annurev-genet-102108-134222 19686080 PMC2830711 · DOI
  2. [2]Kee Y., and D'Andrea A. D. (2012) Molecular pathogenesis and clinical management of Fanconi anemia. J. Clin. Invest. 122, 3799– 3806 10.1172/JCI58321 23114602 PMC3484428 · DOI
  3. [3]Thompson L. H., and Hinz J. M. (2009) Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: mechanistic insights. Mutat. Res. 668, 54– 72 10.1016/j.mrfmmm.2009.02.003 19622404 PMC2714807 · DOI
  4. [4]Wang L. C., Stone S., Hoatlin M. E., and Gautier J. (2008) Fanconi anemia proteins stabilize replication forks. DNA Repair 7, 1973– 1981 10.1016/j.dnarep.2008.08.005 18786657 PMC2596863 · DOI
  5. [5]Arlt M. F., Durkin S. G., Ragland R. L., and Glover T. W. (2006) Common fragile sites as targets for chromosome rearrangements. DNA Repair (Amst.) 25, 1126– 1135 10.1016/j.dnarep.2006.05.010 16807141 · DOI
  6. [6]Howlett N. G., Taniguchi T., Durkin S. G., D'Andrea A. D., and Glover T. W. (2005) The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability. Hum. Mol. Genet. 14, 693– 701 10.1093/hmg/ddi065 15661754 · DOI
  7. [7]Auerbach A. D., and Allen R. G. (1991) Leukemia and pre-leukemia in Fanconi anemia patients. Cancer Genet. Cytogenet. 51, 1– 12 10.1016/0165-4608(91)90002-C 1984836 · DOI
  8. [8]Cioc A. M., Wagner J. E., MacMillan M. L., DeFor T., and Hirsch B. (2010) Diagnosis of myelodysplastic syndrome among a cohort of 119 patients with Fanconi anemia. Am. J. Clin. Pathol. 133, 92– 100 10.1309/AJCP7W9VMJENZOVG 20023263 PMC5467447 · DOI
  9. [9]Hu L., Huang W., Hjort E., and Eklund E. A. (2013) Increased Fanconi C expression contributes to the emergency granulopoiesis response. J. Clin. Invest. 123, 3952– 3966 10.1172/JCI69032 23925293 PMC3754263 · DOI
  10. [10]Lord B. I., Molineux G., Pojda Z., Souza L. M., Mermod J. J., and Dexter T. M. (1991) Myeloid cell kinetics in mice treated with recombinant interleukin-3, granulocyte colony-stimulating factor (CSF), or granulocyte-macrophage CSF in vivo. Blood 77, 2154– 2159 1709372
  11. [12]Panopoulos A. D., and Watowich S. S. (2008) Granulocyte colony stimulating factor: molecular mechanisms of activation during steady state and emergency hematopoiesis. Cytokine 42, 277– 288 18400509 PMC2852428
  12. [14]Panopoulos A. D., Zhang L., Snow J. W., Jones D. M., Smith A. M., El Kasmi K. C., Liu F., Goldsmith M. A., Link D. C., Murray P. J., and Watowich S. S. (2006) Stat3 governs distinct pathways in emergency granulopoiesis and mature neutrophils. Blood 108, 3682– 3690 10.1182/blood-2006-02-003012 16888100 PMC1895456 · DOI · Paper page
  13. [15]Hu L., Huang W., Hjort E. E., Bei L., Platanias L. C., and Eklund E. A. (2016) Interferon consensus sequence binding protein is required to terminate emergency granulopoiesis. J. Biol. Chem. 291, 4107– 4120 10.1074/jbc.M115.681361 26683374 PMC4759186 · DOI
  14. [16]Wang H., Bei L., Shah C. A., Hu L., and Eklund E. A. (2015) HoxA10 terminates emergency granulopoiesis by increasing expression of Triad1. J. Immunol. 194, 5375– 5387 10.4049/jimmunol.1401909 25895533 PMC4433877 · DOI
  15. [17]Saberwal G., Horvath E., Hu L., Zhu C., Hjort E., and Eklund E. A. (2009) The interferon consensus sequence binding protein (ICSBP/IRF8) activates transcription of the FANCF gene during myeloid differentiation. J. Biol. Chem. 284, 33242– 33254 10.1074/jbc.M109.010231 19801548 PMC2785167 · DOI
  16. [18]Kool M., Pétrilli V., De Smedt T., Rolaz A., Hammad H., van Nimwegen M., Bergen I. M., Castillo R., Lambrecht B. N., and Tschopp J. (2008) Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome. J. Immunol. 181, 3755– 3759 10.4049/jimmunol.181.6.3755 18768827 · DOI
  17. [19]Luedde T., Duderstadt M., Streetz K. L., Tacke F., Kubicka S., Manns M. P., and Trautwein C. (2004) C/EBP β isoforms LIP and LAP modulate progression of the cell cycle in the regenerating mouse liver. Hepatology 40, 356– 365 10.1002/hep.20333 15368440 · DOI
  18. [20]Frazer K. A., Pachter L., Poliakov A., Rubin E. M., and Dubchak I. (2004) VISTA: computational tools for comparative genomics. Nucleic Acids Res. 32, W273– 9 10.1093/nar/gkh458 15215394 PMC441596 · DOI
  19. [21]Dubchak I., Brudno M., Loots G. G., Mayor C., Pachter L., Rubin E. M., and Frazer K. A. (2000) Active conservation of noncoding sequences revealed by 3-way species comparisons. Genome Res. 10, 1304– 1306 10.1101/gr.142200 10984448 PMC310906 · DOI
  20. [22]Resende C., Regalo G., Durães C., Pinto M. T., Wen X., Figueiredo C., Carneiro F., and Machado J. C. (2016) Interleukin-1B signaling leads to increased survival of gastric carcinoma cells through a CREB-C/EBPβ-associated mechanism. Gastric Cancer 19, 74– 84 10.1007/s10120-014-0448-x 25740226 · DOI
  21. [23]Horvath C. M., Wen Z., and Darnell J. E. Jr, (1995) A STAT protein domain that determines DNA sequence recognition suggests a novel DNA-binding domain. Genes Dev. 9, 984– 994 10.1101/gad.9.8.984 7774815 · DOI
  22. [24]Ehret G. B., Reichenbach P., Schindler U., Horvath C. M., Fritz S., Nabholz M., and Bucher P. (2001) DNA binding specificity of different STAT proteins: comparison of in vitro specificity with natural target sites. J. Biol. Chem. 276, 6675– 6688 10.1074/jbc.M001748200 11053426 · DOI · Paper page
  23. [25]Decker T., and Kovarik P. (2000) Serine phosphorylation of STATs. Oncogene 19, 2628– 2637 10.1038/sj.onc.1203481 10851062 · DOI · Paper page
  24. [26]Osada S., Yamamoto H., Nishihara T., and Imagawa M. (1996) DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family. J. Biol. Chem. 271, 3891– 3896 10.1074/jbc.271.7.3891 8632009 · DOI
  25. [27]Weinmann A. S., and Farnham P. J. (2002) Identification of unknown target genes of human transcription factors using chromatin immunoprecipitation. Methods 26, 37– 47 10.1016/S1046-2023(02)00006-3 12054903 · DOI
  26. [28]Huang W., Zhou W., Saberwal G., Konieczna I., Horvath E., Katsoulidis E., Platanias L. C., and Eklund E. A. (2010) The interferon consensus sequence binding protein (ICSBP) decreases βcatenin-activity in myeloid cells by repressing GAS2 transcription. Mol. Cell Biol. 30, 4575– 4594 10.1128/MCB.01595-09 20679491 PMC2950519 · DOI
  27. [29]Oda A., Wakao H., and Fujita H. (2002) Calpain is a signal transducer and activator of transcription (STAT) 3 and STAT5 protease. Blood 99, 1850– 1852 10.1182/blood.V99.5.1850 11861304 · DOI
  28. [30]Kisseleva T., Bhattacharya S., Braunstein J., and Schindler C. W. (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285, 1– 24 10.1016/S0378-1119(02)00398-0 12039028 · DOI
  29. [31]Hjort E. E., Huang W., Hu L., and Eklund E. A. (2016) Bcr-abl regulates Stat5 through Shp2, the interferon consensus sequence binding protein (Icsbp/Irf8), growth arrest specific 2 (Gas2) and calpain. Oncotarget 7, 77635– 77650 27769062 PMC5363610
  30. [32]Coppo P., Dusanter-Fourt I., Millot G., Nogueira M. M., Dugray A., Bonnet M. L., Mitjavila-Garcia M. T., Le Pesteur D., Guilhot F., Vainchenker W., Sainteny F., and Turhan A. G. (2003) Constitutive and specific activation of STAT3 by BCR-ABL in embryonic stem cells. Oncogene 22, 4102– 4110 10.1038/sj.onc.1206607 12821944 · DOI
  31. [33]Hayashi Y., Hirai H., Kamio N., Yao H., Yoshioka S., Miura Y., Ashihara E., Fujiyama Y., Tenen D. G., and Maekawa T. (2013) C/EBPβ promotes BCR-ABL-mediated myeloid expansion and leukemic stem cell exhaustion. Leukemia 27, 619– 628 10.1038/leu.2012.258 22948537 PMC4506742 · DOI
  32. [34]Schmidt M., Nagel S., Proba J., Thiede C., Ritter M., Waring J. F., Rosenbauer F., Huhn D., Wittig B., Horak I., and Neubauer A. (1998) Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood 91, 22– 29 9414265
  33. [36]Eklund E. A., Jalava A., and Kakar R. (1998) PU.1, interferon regulatory factor 1, and interferon consensus sequence binding protein cooperate to increase gp91PHOX expression. J. Biol. Chem. 273, 13957– 13965 10.1074/jbc.273.22.13957 9593745 · DOI · Paper page
  34. [37]Yates A., Akanni W., Amode M. R., Barrell D., Billis K., Carvalho-Silva D., Cummins C., Clapham P., Fitzgerald S., Gil L., Girón C. G., Gordon L., Hourlier T., Hunt S. E., Janacek S. H., et al (2016) Ensembl 2016. Nucleic Acids Res. 44, D710– 6 10.1093/nar/gkv1157 26687719 PMC4702834 · DOI
  35. [38]Larrick J. W., Fischer D. G., Anderson S. J., and Koren H. S. (1980) Characterization of a human macrophage-like cell line stimulated to differentiate in vitro: a model of macrophage functions. J. Immunol. 125, 6– 12 7381211
  36. [39]Konieczna I., Horvath E., Wang H., Lindsey S., Saberwal G., Bei L., Huang W., Platanias L., and Eklund E. A. (2008) Constitutive activation of SHP2 cooperates with ICSBP-deficiency to accelerate progression to acute myeloid leukemia. J. Clin. Invest. 118, 853– 867 18246201 PMC2214847
  37. [40]Abe K., Hirai M., Mizuno K., Higashi N., Sekimoto T., Miki T., Hirano T., and Nakajima K. (2001) The YXXQ motif in gp 130 is crucial for STAT3 phosphorylation at Ser727 through an H7-sensitive kinase pathway. Oncogene 20, 3464– 3474 10.1038/sj.onc.1204461 11429693 · DOI · Paper page
  38. [41]Schust J., Sperl B., Hollis A., Mayer T. U., and Berg T. (2006) Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem. Biol. 13, 1235– 1242 10.1016/j.chembiol.2006.09.018 17114005 · DOI · Paper page

Cited by

Sorted by citations

Authors
Shah, C. A., Broglie, L., Hu, L., Bei, L., Huang, W., Dressler, D. B., & Eklund, E. A.
Affiliations
  • Northwestern University (US)
  • Children's Hospital of Wisconsin (US)
Corresponding author
Eklund, Elizabeth A.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2018-03
Volume
293
Issue
11
Pages
3937-3948
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.ra117.000528
PMC
PMC5857980
OpenAlex
W2785524682
Cited by
9
References
3
Citations by year
2025: 1 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 1
FWCI
0.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • HHS NIH National Cancer Institute (NCI) (R01 CA174205)
  • HHS NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK098812)
  • U.S. Department of Veterans Affairs (VA) (BX002067)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
STAT3, C/EBPβ, FANCC, emergency granulopoiesis, IRF8, transcriptional regulation, DNA repair, bone marrow failure, granulocyte production, innate immunity, DNA damage
MeSH terms
Animals, Base Sequence, DNA Repair, Gene Expression Regulation, Granulocytes, Hematopoiesis, Humans, Mice, Inbred C57BL, Promoter Regions, Genetic, Transcription, Genetic, Apoptosis, Sequence Homology, U937 Cells, CCAAT-Enhancer-Binding Protein-beta, STAT3 Transcription Factor, Mice, Fanconi Anemia Complementation Group C Protein

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