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Cited by 69interferon and immune responsesGenomics and Chromatin DynamicsCytokine Signaling Pathways and Interactions

Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

Open access
Kuwata, Takeshi, Gongora, Celine, Kanno, Yuka, Sakaguchi, Kazuyasu, Tamura, Tomohiko, Kanno, Tomohiko, Basrur, Venkatesha, Martinez, Robert +3 more·2002·Molecular and Cellular Biology
DOI 10.1128/mcb.22.21.7439-7448.2002PMC PMC135656
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Abstract

ICSBP (IRF-8) is a transcription factor of the IRF family expressed only in the immune system. It is induced in macrophages by gamma interferon (IFN-gamma) and contributes to macrophage functions. By interacting with Ets family protein PU.1, ICSBP binds to the IRF/Ets composite element and stimulates transcription. ICSBP binds to another DNA element, the IFN-stimulated response element (ISRE), a common target of the IRF family. Limited knowledge as to how ICSBP and other IRF proteins regulate ISRE-dependent transcription in IFN-gamma-activated macrophages is available. By mass-spectrometric analysis of ISRE-bound proteins in macrophages, we identified TEL, another Ets member, as a factor recruited to the element in an IFN-gamma-dependent manner. In vitro analysis with recombinant proteins indicated that this recruitment is due to a direct interaction between ICSBP and TEL, which is enhanced by the presence of ISRE. Significantly, the interaction with TEL in turn resulted in the recruitment of the histone deacetytase HDAC3 to the ISRE, causing increased repression of IFN-gamma-mediated reporter activity through the ISRE. This repression may provide a negative-feedback mechanism operating after the initial transcriptional activation by IFN-gamma. By associating with two different Ets family proteins, ICSBP exerts a dual function in IFN-gamma-dependent gene regulation in an immune system-specific manner.

AI snapshot

Written from the paper’s full text.

TL;DR

In IFNγ-activated macrophages, ICSBP (IRF-8) directly interacts with TEL on the ISRE, recruiting TEL to the element. TEL in turn brings HDAC3 to the ISRE and increases repression of ISRE-dependent transcription, suggesting a negative-feedback mechanism after initial IFNγ activation.

Key findings

  • Mass-spectrometric analysis of ISRE-bound proteins from IFNγ-treated RAW264.7 macrophages identified TEL in bands of ∼62 and ∼58 kDa and ICSBP in a third band; TEL recruitment was IFNγ-dependent and absent from mutant ISRE.
  • Recombinant TEL did not bind the ISRE alone but bound when coincubated with ICSBP, not with IRF-1 or IRF-2; order-of-addition experiments indicated a direct ICSBP-TEL interaction stabilized by the ISRE.
  • Cotransfection of ICSBP and TEL reduced ISRE reporter activity by ∼70%, compared with ∼40% reduction by ICSBP alone; TEL alone had little effect. In 32D cells, TEL plus ICSBP reduced IFNγ-inducible 2′,5′-OAS transcripts to ∼35% of control levels.
  • HDAC3, but not HDAC1 or HDAC2, was recruited to the ISRE in an IFNγ-dependent manner; IFNα/β did not recruit TEL or HDAC3. IRF-1 bound within 1 h, while ICSBP binding increased ∼10-fold by 3 h, coinciding with TEL and HDAC3 recruitment.

Methods

  • DNA affinity binding assays used immobilized wild-type or mutant ISREs incubated with nuclear extracts from RAW264.7 cells treated with IFNγ (100 U/ml) or IFNα/β (1,000 U/ml) for 12 h; bound proteins were analyzed by silver/Coomassie staining, immunoblotting, and tandem mass spectrometry.
  • Recombinant TEL, ICSBP, IRF-1, and IRF-2 were tested for ISRE binding, including order-of-addition assays; GST pull-down assays with TEL and ICSBP deletion mutants mapped interaction domains.
  • ISRE-luciferase reporter assays were performed in RAW cells with ICSBP and/or TEL constructs, and real-time RT-PCR measured 2′,5′-OAS transcripts in 32D cells stably expressing TEL with or without ICSBP.

Limitations

  • The paper does not include a formal limitations section.
  • Evident from the text: standard EMSA did not detect TEL binding to ISRE probes, suggesting TEL associates with relatively low affinity and may dissociate during electrophoresis.
  • Evident from the text: repression required broad regions of TEL beyond those needed for ICSBP binding, and the authors note other explanations are possible, including dependence on proteins other than ICSBP; the paper also suggests microarray analysis would be needed for genome-wide target information.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1128/mcb.22.21.7439-7448.2002

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 65 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § RESULTS

    TEL expression levels did not alter following IFNγ treatment in RAW cells.

    “the antibody recognized two species of TEL in RAWcell extracts that were present in similar amounts before and after IFN𝛄 treatment, indicating that TEL expression levels did not alter following IFN𝛄 treatment.”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    TEL is recruited to the ISRE in an IFNγ-dependent manner in macrophages.

    “By mass-spectrometric analysis of ISRE-bound proteins in macrophages, we identified TEL, another Ets member, as a factor recruited to the element in an IFN𝛄 -dependent manner.”
    • Also stated in: § RESULTS · plain
      “Taken together, the results of this analysis identify TEL as a factor recruited to the ISRE upon IFN𝛄 treatment.”
    Quote in the paperSubstantial claim
  • Findingown data
    § RESULTS

    TEL did not bind to the ISRE in untreated RAW cell extracts.

    “neither TEL species bound to the ISRE in untreated samples.”
    Quote in the paperSubstantial claim
  • Findingown data
    § RESULTS

    TEL was not found on the mutant ISRE regardless of IFNγ treatment.

    “TEL was not found on the mutant ISRE, regardless of IFN𝛄 treatment.”
    Quote in the paperSubstantial claim
  • Findingown data
    § RESULTS

    K79E, containing a point mutation in the DBD known to be critical for ISRE binding, failed to bind to TEL.

    “Interestingly, K79E, containing a point mutation in the DBD known to be critical for ISRE binding, failed to bind to TEL.”
    Quote in the paperSubstantial claim
  • May combine two claims. 42
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data
    § RESULTS

    ICSBP and IRF-1 levels were enhanced after IFNγ treatment.

    “levels of ICSBP and IRF-1 were enhanced after IFN𝛄 treatment (compare -and + input lanes in Fig. 1B), consistent with IFN𝛄 induction of the IRF proteins (22, 53).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] 22. Kantakamalakul, W., A. D. Politis, S. Marecki, T. Sullivan, K. Ozato, M. J. Fenton, and S. N. Vogel. 1999. Regulation of IFN consensus sequence binding protein expression in murine macrophages. J. Immunol. 162: 7417-7425. source

      Not checked in the free run.

    • cites [53] 53. Wang, I. M., J. C. Blanco, S. Y. Tsai, M. J. Tsai, and K. Ozato. 1996. Interferon regulatory factors and TFIIB cooperatively regulate interferonresponsive promoter activity in vivo and in vitro. Mol. Cell. Biol. 16: 63136324. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data
    § RESULTS

    TEL was not recruited to the ISRE when added alone prior to addition of ICSBP, nor when ICSBP was added before TEL.

    “TEL was not recruited to the ISRE when added alone prior to the addition of ICSBP. Likewise TEL was not recruited when ICSBP was added before TEL.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    The reporter activities obtained with Δ55-245 and ΔEts did not significantly differ from those with ICSBP alone, indicating that these deletion mutants did not have repressive activity.

    “The reporter activities obtained with 𝚫 55-245 and 𝚫 Ets did not significantly differ from those with ICSBP alone, indicating that these deletion mutants did not have a repressive activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Wild-type TEL, when cotransfected with ICSBP, repressed reporter activity by ∼65% but did not repress reporter activity when transfected alone.

    “wildtype TEL, when cotransfected with ICSBP, repressed reporter activity by ∼ 65% but did not repress reporter activity when transfected alone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    ICSBP did not bind to the C-terminal deletion mutants 1-245, 1-332, and 1-419, or to ΔEts.

    “it did not bind to the C-terminal deletion mutants, 1-245, 1-332, and 1-419, or to 𝚫 Ets”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Mutations of both halves of the GAAA repeat greatly diminished binding of ICSBP and IRF-1 and completely abolished TEL recruitment.

    “mutations of both halves of the GAAA greatly diminished the binding of ICSBP and IRF-1 and completely abolished TEL recruitment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    ICSBP bound to Δ55-245 and Δ55-332, although binding to the latter was weaker.

    “Similarly, ICSBP bound to 𝚫 55-245 and 𝚫 55-332, which lack the internal region, although binding to the latter was weaker than binding to the former.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    TEL did not bind to the element when coincubated with IRF-1 plus IRF-2 but bound well when incubated with ICSBP plus IRF-1 or IRF-2.

    “TEL did not bind to the element when coincubated with IRF-1 plus IRF-2 but bound well when incubated with ICSBP plus IRF-1 or IRF-2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Standard EMSA did not reveal binding of recombinant TEL to ISRE probes in the presence or absence of ICSBP, and TEL binding was not detected in EMSA with RAW cell extracts.

    “the standard electrophoretic gel mobility shift assays (EMSA) did not reveal the binding of recombinant TEL to ISRE probes in the presence or absence of ICSBP. TEL binding was not detected in EMSA with RAW cell extracts either (not shown)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § RESULTS

    TEL binding appeared somewhat weaker when incubated in the presence of IRF-2 than when incubated in the presence of IRF-1.

    “TEL binding appeared somewhat weaker when TEL was incubated in the presence of IRF-2 than when it was incubated in the presence of IRF-1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Full-length ICSBP and all C-terminal deletion mutants 1-390, 1-356, 1-305, and 1-254 bound to TEL but not control GST.

    “Full-length ICSBP and all C-terminal deletion mutants, 1-390, 1-356, 1-305, and 1-254, bound to TEL but not control GST.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data
    § RESULTS

    The reporter activity observed with Δ55-332 was slightly higher than that due to ICSBP alone, suggesting that this deletion might have interfered with the activity of endogenous TEL.

    “The reporter activity observed with 𝚫 55-332 was slightly higher than those due to ICSBP alone, suggesting that this deletion might have interfered with the activity of endogenous TEL.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    TEL is overexpressed in the TEL clone while almost undetectable in the control clone.

    “Immunoblot assays in Fig. 5A show that TEL is overexpressed in the TEL clone while it is almost undetectable in the control clone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    HDAC1, HDAC2, and HDAC3 were all expressed in RAW cells and their levels remained similar before and after IFNγ treatment.

    “As seen in Fig. 6A, HDAC1, HDAC2, and HDAC3 were all expressed in RAW cells and their levels remained similar before and after IFN𝛄 treatment”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § DISCUSSION

    ICSBP and TEL, when added together, showed an increase in apparent ISRE binding activity, suggesting that the TEL-ICSBP interaction is stabilized by the ISRE.

    “In addition, ICSBP and TEL, when added together, showed an increase in apparent ISRE binding activity, suggesting that the TEL-ICSBP interaction is stabilized by the ISRE.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    TEL was not recruited to the ISRE following IFNα/β treatment, although ICSBP, IRF-1, and IRF-2 bound to the ISRE.

    “As seen in Fig. 6B, TEL was not recruited to the ISRE following IFN𝛂 / 𝛃 treatment, although ICSBP, IRF-1, and IRF-2 bound to the ISRE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Neither HDAC3 nor TEL bound to the mutant ISRE.

    “Supporting the specificity of HDAC3 recruitment, neither HDAC3 nor TEL bound to the mutant ISRE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    ICSBP was essentially undetectable in the control clone but was induced at a modest level by IFNγ.

    “ICSBP was also essentially undetectable in the control clone but was induced at a modest level by IFN𝛄 .”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    Transcript levels in the TEL clone were also increased upon IFNγ treatment, with kinetics similar to those for the control cells.

    “Transcript levels in the TEL clone were also increased upon IFN𝛄 treatment, with kinetics similar to those for the control cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § RESULTS

    At 1 h, the binding of ICSBP was very low, with little recruitment of TEL and HDAC3.

    “At that time, the binding of ICSBP was very low, with little recruitment of TEL and HDAC3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given
    § RESULTS

    ICSBP was constitutively expressed in the TEL-plus-ICSBP clone, and the expression was not affected by IFNγ treatment.

    “ICSBP was constitutively expressed in the TEL-plus-ICSBP clone, and the expression was not affected by IFN𝛄 treatment, as expected.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Findingnone given
    § RESULTS

    32D cells are a murine myeloid progenitor cell line where expression of endogenous ICSBP and TEL is low.

    “32D cells are a murine myeloid progenitor cell line where expression of endogenous ICSBP and TEL is low.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § DISCUSSION

    Only HDAC3, not HDAC1 and HDAC2, was recruited to the ISRE.

    “It is noteworthy that only HDAC3, not HDAC1 and HDAC2, was recruited to the ISRE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § DISCUSSION

    In experiments where TEL and ICSBP were ectopically expressed, ISRE-dependent transcription was repressed even in the absence of IFNγ addition, although repression was greater following IFNγ addition.

    “In these experiments, where TEL and ICSBP were ectopically expressed, ISRE-dependent transcription was repressed even in the absence of IFN𝛄 addition, although repression was greater following IFN𝛄 addition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § DISCUSSION

    The binding of IRF-1, a transcriptional activator, precedes the recruitment of TEL and HDAC3, which coincides with ICSBP binding.

    “results of kinetics studies shown in Fig. 6C indicated that the binding of IRF-1, a transcriptional activator, precedes the recruitment of TEL and HDAC3, which coincides with ICSBP binding.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    The PU.1-ICSBP interaction is DNA directed and facilitated by EICE.

    “Analogous to the PU.1-Pip interaction, the PU.1-ICSBP interaction is DNA directed and facilitated by EICE (4, 38).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] 4. Brass, A. L., E. Kehrli, C. F. Eisenbeis, U. Storb, and H. Singh. 1996. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 10: 2335-2347. source

      Not checked in the free run.

    • cites [38] 38. Perkel, J. M., and M. L. Atchison. 1998. A two-step mechanism for recruitment of Pip by PU.1. J. Immunol. 160: 241-252. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § RESULTS

    TEL and ICSBP directly interact with each other to bind to the ISRE.

    “These results indicate that TEL and ICSBP directly interact with each other to bind to the ISRE.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    TEL has an oligomerization domain in the N terminus that is conserved in several Ets members but not in PU.1.

    “It also has the oligomerization domain (also called the pointed [PNT] domain, B domain, or HLH domain) in the N terminus that is conserved in several Ets members, but not in PU.1 (33, 39).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] 33. Mavrothalassitis, G., and J. Ghysdael. 2000. Proteins of the ETS family with transcriptional repressor activity. Oncogene 19: 6524-6532. source

      Not checked in the free run.

    • cites [39] 39. Poirel, H., C. Oury, C. Carron, E. Duprez, Y. Laabi, A. Tsapis, S. P. Romana, M. Mauchauffe, M. Le Coniat, R. Berger, J. Ghysdael, and O. A. Bernard. 1997. The TEL gene products: nuclear phosphoproteins with DNA binding properties. Oncogene 14: 349-357. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    TEL has a classic Ets domain in the C terminus and binds to the Ets site with a core motif of GGAA/T.

    “TEL has a classic Ets domain in the C terminus and binds to the Ets site, with a core motif of GGAA/T (44).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] 44. Sementchenko, V. I., and D. K. Watson. 2000. Ets target genes: past, present and future. Oncogene 19: 6533-6548. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    Activation of EICE-dependent transcription appears to involve phosphorylation of PU.1 as well as ICSBP.

    “Activation of EICE-dependent transcription appears to involve phosphorylation of PU.1 as well as ICSBP (28, 45).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] 28. Lodie, T. A., R. Savedra, Jr., D. T. Golenbock, C. P. Van Beveren, R. A. Maki, and M. J. Fenton. 1997. Stimulation of macrophages by lipopolysaccharide alters the phosphorylation state, conformation, and function of PU.1 via activation of casein kinase II. J. Immunol. 158: 1848-1856. source

      Not checked in the free run.

    • cites [45] 45. Sharf, R., D. Meraro, A. Azriel, A. M. Thornton, K. Ozato, E. F. Petricoin, A. C. Larner, F. Schaper, H. Hauser, and B. Z. Levi. 1997. Phosphorylation events modulate the ability of interferon consensus sequence binding protein to interact with interferon regulatory factors and to bind DNA. J. Biol. Chem. 272: 9785-9792. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    Activation of EICE-dependent transcription may in part be due to recruitment of coactivator/histone acetylase CBP/p300, since CBP/p300 can interact with PU.1 but not ICSBP.

    “This activation may in part be due to the recruitment of coactivator/ histone acetylase CBP/p300, since CBP/p300 can interact with PU.1 (but not ICSBP) (32, 59).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] 32. Masumi, A., I. M. Wang, B. Lefebvre, X. J. Yang, Y. Nakatani, and K. Ozato. 1999. The histone acetylase PCAF is a phorbol-ester-inducible coactivator of the IRF family that confers enhanced interferon responsiveness. Mol. Cell. Biol. 19: 1810-1820. source

      Not checked in the free run.

    • cites [59] 59. Yamamoto, H., F. Kihara-Negishi, T. Yamada, Y. Hashimoto, and T. Oikawa. 1999. Physical and functional interactions between the transcription factor PU.1 and the coactivator CBP. Oncogene 18: 1495-1501. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    Previous reporter analysis indicated that ICSBP is a repressor of ISRE-dependent transcription.

    “Likewise, previous reporter analysis indicated that ICSBP is a repressor of ISRE-dependent transcription (36, 57).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] 36. Nelson, N., M. S. Marks, P. H. Driggers, and K. Ozato. 1993. Interferon consensus sequence-binding protein, a member of the interferon regulatory factor family, suppresses interferon-induced gene transcription. Mol. Cell. Biol. 13: 588-599. source

      Not checked in the free run.

    • cites [57] 57. Weisz, A., P. Marx, R. Sharf, E. Appella, P. H. Driggers, K. Ozato, and B. Z. Levi. 1992. Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. J. Biol. Chem. 267: 25589-25596. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § RESULTS

    TEL associates with the ISRE with relatively low affinity and dissociates from the complex during electrophoresis.

    “suggesting that TEL associates with the ISRE with a relatively low affinity and dissociates from the complex during electrophoresis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    TEL represses transcription through the Ets site, and repression may be attributed to recruitment of mSin3A, corepressor N-CoR, and histone deacetylase HDAC3.

    “TEL represses transcription through the Ets site, and repression may be attributed to the recruitment of mSin3A, corepressor N-CoR, and histone deacetylase HDAC3 (7, 14, 29, 33, 55).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [7] 7. Chakrabarti, S. R., and G. Nucifora. 1999. The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A. Biochem. Biophys. Res. Commun. 264: 871-877. source

      Not checked in the free run.

    • cites [14] 14. Fenrick, R., J. M. Amann, B. Lutterbach, L. Wang, J. J. Westendorf, J. R. Downing, and S. W. Hiebert. 1999. Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein. Mol. Cell. Biol. 19: 6566-6574. source

      Not checked in the free run.

    • cites [29] 29. Lopez, R. G., C. Carron, C. Oury, P. Gardellin, O. Bernard, and J. Ghysdael. 1999. TEL is a sequence-specific transcriptional repressor. J. Biol. Chem. 274: 30132-30138. source

      Not checked in the free run.

    • cites [33] 33. Mavrothalassitis, G., and J. Ghysdael. 2000. Proteins of the ETS family with transcriptional repressor activity. Oncogene 19: 6524-6532. source

      Not checked in the free run.

    • cites [55] 55. Wang, L., and S. W. Hiebert. 2001. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene 20: 3716-3725. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    The PU.1-ICSBP complex and the PU.1-Pip complex act as stimulators of EICE-mediated transcription.

    “The PU.1ICSBP complex and the PU.1-Pip complex are shown to act as a stimulators of EICE-mediated transcription (4, 40).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] 4. Brass, A. L., E. Kehrli, C. F. Eisenbeis, U. Storb, and H. Singh. 1996. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 10: 2335-2347. source

      Not checked in the free run.

    • cites [40] 40. Pongubala, J. M., and M. L. Atchison. 1997. PU.1 can participate in an active enhancer complex without its transcriptional activation domain. Proc. Natl. Acad. Sci. USA 94: 127-132. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § RESULTS

    TEL does not bind to the ISRE by itself but binds to it in the presence of ICSBP, suggesting that recruitment of TEL to the ISRE is dependent on ICSBP.

    “These results indicate that TEL does not bind to the ISRE by itself but binds to it in the presence of ICSBP, suggesting that recruitment of TEL to the ISRE is dependent on ICSBP.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    ICSBP and Pip (IRF-4) are expressed only in the immune system.

    “Although the majority of IRF family members are expressed broadly in many cell types, ICSBP and another member, Pip (IRF-4), are expressed only in the immune system (4, 12, 49).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] 4. Brass, A. L., E. Kehrli, C. F. Eisenbeis, U. Storb, and H. Singh. 1996. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 10: 2335-2347. source

      Not checked in the free run.

    • cites [12] 12. Driggers, P. H., D. L. Ennist, S. L. Gleason, W. H. Mak, M. S. Marks, B. Z. Levi, J. R. Flanagan, E. Appella, and K. Ozato. 1990. An interferon gammaregulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc. Natl. Acad. Sci. USA 87: 3743-3747. source

      Not checked in the free run.

    • cites [49] 49. Tamura, T., and K. Ozato. 2002. ICSBP(IRF-8): its regulatory role in the development of myeloid cells. J. Interferon Cytokine. Res. 22: 145-152. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § RESULTS

    Both the extreme C-terminal domain and the Ets domain of TEL are required for interacting with ICSBP.

    “indicating that both the extreme C-terminal domain and the Ets domain are required for interacting with ICSBP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given
    § Gamma Interferon Triggers Interaction between ICSBP (IRF-8) and TEL, Recruiting the Histone Deacetylase HDAC3 to the Interferon-Responsive Element

    ICSBP binds to the IRF/Ets composite element and stimulates transcription by interacting with PU.1.

    “By interacting with Ets family protein PU.1, ICSBP binds to the IRF/Ets composite element and stimulates transcription.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § RESULTS

    In many cell types HDAC1 and HDAC2 are more abundant than HDAC3.

    “In many cell types HDAC1 and HDAC2 are more abundant than HDAC3 (9, 20, 24).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] 9. Cress, W. D., and E. Seto. 2000. Histone deacetylases, transcriptional control, and cancer. J. Cell Physiol. 184: 1-16.

      Not checked in the free run.

    • cites [20] 20. Humphrey, G. W., Y. Wang, V. R. Russanova, T. Hirai, J. Qin, Y. Nakatani, and B. H. Howard. 2001. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276: 6817-6824. source

      Not checked in the free run.

    • cites [24] 24. Khochbin, S., A. Verdel, C. Lemercier, and D. Seigneurin-Berny. 2001. Functional significance of histone deacetylase diversity. Curr. Opin. Genet. Dev. 11: 162-166. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    PU.1 interacts with Pip, another member of the IRF family, in a phosphorylation-dependent manner.

    “In addition to ICSBP, PU.1 interacts with Pip, another member of the IRF family, in a phosphorylation-dependent manner (40).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] 40. Pongubala, J. M., and M. L. Atchison. 1997. PU.1 can participate in an active enhancer complex without its transcriptional activation domain. Proc. Natl. Acad. Sci. USA 94: 127-132. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § DISCUSSION

    The PU.1-ICSBP interaction is dependent on the IAD domain in the C-terminal region, although the DBD is also required.

    “the PU.1-ICSBP interaction is dependent on the IAD domain in the C-terminal region, although the DBD is also required for this interaction (5, 38).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] 5. Brass, A. L., A. Q. Zhu, and H. Singh. 1999. Assembly requirement of PU.1-Pip(IRF-4) activator complexes: inhibiting function in vivo using fused dimers. EMBO J. 18: 977-991. source

      Not checked in the free run.

    • cites [38] 38. Perkel, J. M., and M. L. Atchison. 1998. A two-step mechanism for recruitment of Pip by PU.1. J. Immunol. 160: 241-252. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    ICSBP has been known to interact with PU.1, a hematopoietic-cell-specific member of the Ets family.

    “ICSBP has been known to interact with PU.1, a hematopoietic-cellspecific member of the Ets family (4, 5, 38).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [4] 4. Brass, A. L., E. Kehrli, C. F. Eisenbeis, U. Storb, and H. Singh. 1996. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 10: 2335-2347. source

      Not checked in the free run.

    • cites [5] 5. Brass, A. L., A. Q. Zhu, and H. Singh. 1999. Assembly requirement of PU.1-Pip(IRF-4) activator complexes: inhibiting function in vivo using fused dimers. EMBO J. 18: 977-991. source

      Not checked in the free run.

    • cites [38] 38. Perkel, J. M., and M. L. Atchison. 1998. A two-step mechanism for recruitment of Pip by PU.1. J. Immunol. 160: 241-252. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § RESULTS

    TEL also interacts with mSin3A as well as SMRT and N-CoR.

    “TEL also interacts with mSin3A as well as SMRT and N-CoR (7, 14).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] 7. Chakrabarti, S. R., and G. Nucifora. 1999. The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A. Biochem. Biophys. Res. Commun. 264: 871-877. source

      Not checked in the free run.

    • cites [14] 14. Fenrick, R., J. M. Amann, B. Lutterbach, L. Wang, J. J. Westendorf, J. R. Downing, and S. W. Hiebert. 1999. Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein. Mol. Cell. Biol. 19: 6566-6574. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § RESULTS

    A number of DNA binding transcription factors repress transcription by recruiting histone deacetylases to the promoter.

    “A number of DNA binding transcription factors repress transcription by recruiting histone deacetylases to the promoter (9, 24).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 9. Cress, W. D., and E. Seto. 2000. Histone deacetylases, transcriptional control, and cancer. J. Cell Physiol. 184: 1-16.

      Not checked in the free run.

    • cites [24] 24. Khochbin, S., A. Verdel, C. Lemercier, and D. Seigneurin-Berny. 2001. Functional significance of histone deacetylase diversity. Curr. Opin. Genet. Dev. 11: 162-166. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § DISCUSSION

    The TEL gene encodes at least two phosphoproteins, both isoforms being subject to common and distinct phosphorylation events.

    “the TEL gene encodes at least two phosphoproteins, both isoforms being subject to common and distinct phosphorylation events (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] 39. Poirel, H., C. Oury, C. Carron, E. Duprez, Y. Laabi, A. Tsapis, S. P. Romana, M. Mauchauffe, M. Le Coniat, R. Berger, J. Ghysdael, and O. A. Bernard. 1997. The TEL gene products: nuclear phosphoproteins with DNA binding properties. Oncogene 14: 349-357. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § RESULTS

    mSin3A, SMRT, and N-CoR are part of large histone deacetylase complexes.

    “The last three factors are part of the large histone deacetylase complexes (20, 51, 60).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] 20. Humphrey, G. W., Y. Wang, V. R. Russanova, T. Hirai, J. Qin, Y. Nakatani, and B. H. Howard. 2001. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276: 6817-6824. source

      Not checked in the free run.

    • cites [51] 51. Tong, J. K., C. A. Hassig, G. R. Schnitzler, R. E. Kingston, and S. L. Schreiber. 1998. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395: 917-921. source

      Not checked in the free run.

    • cites [60] 60. Zhang, Y., H. H. Ng, H. Erdjument-Bromage, P. Tempst, A. Bird, and D. Reinberg. 1999. Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes Dev. 13: 19241935. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § RESULTS

    TEL interacts with HDAC3, and this interaction is thought to account for transcriptional repression through the Ets site.

    “Indeed, TEL interacts with HDAC3, and this interaction is thought to account for transcriptional repression through the Ets site (55).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] 55. Wang, L., and S. W. Hiebert. 2001. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene 20: 3716-3725. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § DISCUSSION

    TEL-mediated repression may be an example of negative regulation acting at the level of transcription, which may be particularly important for ISRE-carrying genes that are normally stimulated by IFNα/β.

    “The TELmediated repression may be an example of negative regulation acting at the level of transcription, which may be particularly important for ISRE-carrying genes that are normally stimulated by IFN𝛂 / 𝛃 (47).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] 47. Stark, G. R., I. M. Kerr, B. R. Williams, R. H. Silverman, and R. D. Schreiber. 1998. How cells respond to interferons. Annu. Rev. Biochem. 67: 227-264. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § DISCUSSION

    Recent studies indicate that the corepressors N-CoR and SMRT are preferentially assembled into the HDAC3 complex, but not into the HDAC1 or HDAC2 complex, suggesting that HDAC3 has a functional activity distinct from those of other class I histone deacetylases.

    “recent studies indicate that the corepressors N-CoR and SMRT are preferentially assembled into the HDAC3 complex, but not into the HDAC1 or HDAC2 complex, suggesting that HDAC3 has a functional activity distinct from those of other class I histone deacetylases (27, 58).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [27] 27. Li, J., J. Wang, Z. Nawaz, J. M. Liu, J. Qin, and J. Wong. 2000. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19: 4342-4350. source

      Not checked in the free run.

    • cites [58] 58. Wen, Y. D., V. Perissi, L. M. Staszewski, W. M. Yang, A. Krones, C. K. Glass, M. G. Rosenfeld, and E. Seto. 2000. The histone deacetylase-3 complex contains nuclear receptor corepressors. Proc. Nat. Acad. Sci. USA 97: 72027207. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    The results are consistent with the previous report by Wang and Hiebert showing that TEL interacts with HDAC3 and represses Ets-dependent transcription.

    “Our results are consistent with the previous report by Wang and Hiebert (55) showing that TEL interacts with HDAC3 and represses Ets-dependent transcription.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] 55. Wang, L., and S. W. Hiebert. 2001. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene 20: 3716-3725. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    Activation of cytokine signaling is coupled with multiple layers of negative regulation to ensure timely down-regulation of signaling, as exemplified by the SOCS system.

    “Activation of cytokine signaling is coupled with multiple layers of negative regulation to ensure timely down-regulation of signaling, as exemplified by the SOCS system (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] 17. Greenhalgh, C. J., and D. J. Hilton. 2001. Negative regulation of cytokine signaling. J. Leukoc. Biol. 70: 348-356. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § DISCUSSION

    ICSBP and PU.1 activate transcription through EICE and related elements in IFNγ-stimulated macrophages.

    “Accumulating evidence indicates that ICSBP and PU.1 activate transcription through EICE and related elements in IFN𝛄 -stimulated macrophages, as reported for genes encoding the respiratory oxidases gp91 phox and p67 phox and interleukin-1 𝛃 (IL-1 𝛃 ) (13, 23, 30).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] 13. Eklund, E. A., A. Jalava, and R. Kakar. 1998. PU.1, interferon regulatory factor 1, and interferon consensus sequence-binding protein cooperate to increase gp91(phox) expression. J. Biol. Chem. 273: 13957-13965. source

      Not checked in the free run.

    • cites [23] 23. Kautz, B., R. Kakar, E. David, and E. A. Eklund. 2001. SHP1 proteintyrosine phosphatase inhibits gp91PHOX and p67PHOX expression by inhibiting interaction of PU.1, IRF1, interferon consensus sequence-binding protein, and CREB-binding protein with homologous cis elements in the CYBB and NCF2 genes. J. Biol. Chem. 276: 37868-37878. source

      Not checked in the free run.

    • cites [30] 30. Marecki, S., M. L. Atchison, and M. J. Fenton. 1999. Differential expression and distinct functions of IFN regulatory factor 4 and IFN consensus sequence binding protein in macrophages. J. Immunol. 163: 2713-2722. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § DISCUSSION

    This activation seems to involve other factors, notably the coactivator/histone acetylase CBP/p300, with which PU.1 is shown to interact.

    “This activation seems to involve other factors, notably the coactivator/histone acetylase CBP/p300, with which PU.1 is shown to interact (59).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] 59. Yamamoto, H., F. Kihara-Negishi, T. Yamada, Y. Hashimoto, and T. Oikawa. 1999. Physical and functional interactions between the transcription factor PU.1 and the coactivator CBP. Oncogene 18: 1495-1501. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § DISCUSSION

    ICSBP assumes a dual activity in IFNγ-stimulated macrophages: with PU.1 it cooperatively activates a certain set of genes, and by forming a complex with TEL it represses gene expression through the ISRE.

    “Combining these results, it appears that ICSBP assumes a dual activity in IFN𝛄 -stimulated macrophages: on one hand ICSBP and PU.1 cooperatively activate a certain set of genes. On the other hand, by forming a complex with TEL, ICSBP represses gene expression through the ISRE”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § DISCUSSION

    The ICSBP-TEL interaction and PU.1-ICSBP interaction lead to opposite outcomes in transcription: the former causes increased repression, the latter results in transcriptional activation.

    “Another notable difference between the ICSBP-TEL interaction and that of PU.1-ICSBP is that they lead to opposite outcomes in transcription, i.e., while the former causes increased repression, the latter results in transcriptional activation.”
    Quote in the paperSubstantial claim
56 of 56

  • The paper relies on this without support.

    Limited knowledge is available about how ICSBP and other IRF proteins regulate ISRE-dependent transcription in IFNγ-activated macrophages.

    “Limited knowledge as to how ICSBP and other IRF proteins regulate ISRE-dependent transcription in IFN𝛄 -activated macrophages is available.”

  • The paper relies on this without support.

    It is not clear whether repression of ISRE-mediated transcription by ICSBP, observed previously in nonimmune cells, is relevant to activated macrophages.

    “it has not been quite clear whether repression of ISRE-mediated transcription by ICSBP, observed previously in nonimmune cells (36, 57), is relevant to activated macrophages.”

  • The paper relies on this without support.

    It is unclear whether activated macrophages have a unique mechanism of regulating ISRE-dependent transcription and, if so, what role ICSBP plays.

    “It has also been unclear whether activated macrophages have a unique mechanism of regulating ISRE-dependent transcription and, if so, what role ICSBP plays.”

  • The paper relies on this without support.

    The ISRE does not have an Ets site to which an Ets family member could bind.

    “However, the ISRE does not have an Ets site to which an Ets family member could bind.”

  • The paper relies on this without support.

    HDAC3 is a member of the class I histone deacetylases, which include HDAC1 and HDAC2.

    “HDAC3 is a member of the class I histone deacetylases, which include HDAC1 and HDAC2.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Second ICSBP peptide length conflicts with its assigned positions

    Minor

    The listed peptide has 13 amino acids, but positions 362 through 373 encompass only 12 amino acids.

  • Figure 5A gives conflicting IFNγ treatment durations

    Minor

    The Figure 5A caption says the cells were treated for 6 h, while the results text says the clones used for Figure 5A were treated for 12 h.

  • ICSBP peptide length conflicts with its assigned positions

    Minor

    The listed peptide has 13 amino acids, but positions 45 through 58 encompass 14 amino acids.

3 of 3

The citation lists haven’t been fetched yet

References 61 · Cited by 69

Authors
Kuwata, T., Gongora, C., Kanno, Y., Sakaguchi, K., Tamura, T., Kanno, T., Basrur, V., Martinez, R., Appella, E., Golub, T., & Ozato, K.
Affiliations
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
  • Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development
  • National Institutes of Health (US)
  • Harvard University (US)
Corresponding author
Ozato, Keiko
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2002-11
Volume
22
Issue
21
Pages
7439-7448
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.22.21.7439-7448.2002
PMC
PMC135656
OpenAlex
W2161028989
Semantic Scholar
5a015cee08f4a3457853a71288c64ff11e89dac1
Cited by
69
References
61
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 4 · 2014: 2 · 2013: 1 · 2012: 1
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Association pour la Recherche sur le Cancer
  • National Institutes of Health
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
IRF8, interferon-gamma, TEL, ETS transcription factors, HDAC3, histone deacetylation, interferon-stimulated response element, macrophages, transcriptional repression, negative feedback, transcriptional regulation
MeSH terms
ETS Translocation Variant 6 Protein, Interferon Regulatory Factor-8, Histone Deacetylase 3, Animals, Cell Line, Cell Nucleus, DNA, DNA-Binding Proteins, Gene Expression Regulation, Glutathione Transferase, Histone Deacetylases, Interferon-gamma, Interferons, Macrophages, Models, Biological, Mutation, Protein Binding, Repressor Proteins, RNA, Messenger, Mass Spectrometry, Gene Deletion, Protein Structure, Tertiary, Genes, Reporter, Reverse Transcriptase Polymerase Chain Reaction, Proto-Oncogene Proteins c-ets, Interferon Regulatory Factors, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

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