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Event: 1717

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Suppression of STAT5 binding to cytokine gene promoters

Short name

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Biological Context

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Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
T cell

Organ term

Organ term
immune system

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
negative regulation of DNA binding	protein-DNA complex	decreased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Immune dysfunction induced by JAK3 inhibition	KeyEvent	Yasuhiro Yoshida (send email)	Under development: Not open for comment. Do not cite	Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Mus musculoides	Mus musculoides	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

IL-2 and other cytokines rapidly activate JAK1 and JAK3 (Beadling, et al. 1994) in peripheral blood lymphocytes. The activation of JAK kinases and STAT proteins by IL-2 and IFN-α does not include the T cell antigen receptor in human T lymphocytes (Beadling, et al. 1994). After activation of JAKs, latent STAT transcription factors induce dimeric STAT proteins (Gaffen, et al. 1995). These proteins then translocate to the nucleus, where they bind to and regulate the transcriptional activation of the promoters of target genes. Dimeric STAT proteins can bind to the palindromic gamma interferon-activated (GAS) sequence TTCNmGAA, where m is 3 for all the STATs, except STAT6. The latter can additionally bind to GAS motifs. The m for STAT6 denotes 4 (Darnell 1997, Decker, et al. 1997, Ihle 1996, Leonard and O'Shea 1998).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

EMSA using nuclear extracts and specific oligonucleotides, including transcription factor binding sites, such as cytokine-inducible SH2-containing protein (CIS) gene promoters, are useful to evaluate DNA binding activity (Johnston, et al. 1995). Activated STAT5 binds to specific DNA-probes in splenocytes (Liu, et al. 2010). A cell-permeable non-peptidic nicotinoyl hydrazone compound selectively targets the SH2 domain of STAT5 (IC50 = 47 µM against STAT5b SH2 domain EPO peptide binding activity), with markedly less recognition of the SH2 domain of STAT1, STAT3, or Lck (IC50 > 500 µM). This compound inhibited STAT5/STAT5 DNA binding activity in K562 nuclear extract and inhibited IFN-α-stimulated STAT5 tyrosine phosphorylation in Daudi cells, but not STAT1 or STAT3 (Muller, et al. 2008).

Nuclear extracts were prepared from untreated YT cells or cells treated with recombinant IL-2 (2 nM) for 30 min at 37°C. EMSA was performed using glycerol-containing 5% polyacrylamide gels (29:1) containing 0.5× Tris-borate-EDTA buffer. For supershift assays, nuclear extracts were preincubated for 10 min with antibodies against STAT5. Oligonucleotide sequences from PRRIFV have been used as probes (Maeshima, et al. 2012). Other authors described a supershift ESMA that involved preincubating whole-cell extract with 3 μL of pan-STAT5 antiserum that recognizes both STAT5a and STAT5b. Electrophoresis was carried out at room temperature using 5% or 6% polyacrylamide gels (Heidt, et al. 2010).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

STAT5 is expressed in hematopoietic cells, such as T and B cells from humans, rodents, and other mammalian species (Gilmour, et al. 1995).

References

List of the literature that was cited for this KE description. More help

Beadling C, Guschin D, Witthuhn BA, Ziemiecki A, Ihle JN, Kerr IM, Cantrell DA. 1994. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. EMBO J 13:5605-5615.

Darnell JE, Jr. 1997. STATs and gene regulation. Science 277:1630-1635.

Decker T, Kovarik P, Meinke A. 1997. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res 17:121-134. DOI: 10.1089/jir.1997.17.121.

Gaffen SL, Lai SY, Xu W, Gouilleux F, Groner B, Goldsmith MA, Greene WC. 1995. Signaling through the interleukin 2 receptor beta chain activates a STAT-5-like DNA-binding activity. Proc Natl Acad Sci U S A 92:7192-7196.

Gilmour KC, Pine R, Reich NC. 1995. Interleukin 2 activates STAT5 transcription factor (mammary gland factor) and specific gene expression in T lymphocytes. Proc Natl Acad Sci U S A 92:10772-10776. DOI: 10.1073/pnas.92.23.10772.

Heidt S, Roelen DL, Eijsink C, Eikmans M, van Kooten C, Claas FH, Mulder A. 2010. Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clin Exp Immunol 159:199-207. DOI: 10.1111/j.1365-2249.2009.04051.x.

Ihle JN. 1996. STATs: signal transducers and activators of transcription. Cell 84:331-334.

Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD, et al. 1995. Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proc Natl Acad Sci U S A 92:8705-8709.

Leonard WJ, O'Shea JJ. 1998. Jaks and STATs: biological implications. Annu Rev Immunol 16:293-322. DOI: 10.1146/annurev.immunol.16.1.293.

Liu J, Yoshida Y, Kunugita N, Noguchi J, Sugiura T, Ding N, Arashidani K, Fujimaki H, Yamashita U. 2010. Thymocytes are activated by toluene inhalation through the transcription factors NF-kappaB, STAT5 and NF-AT. J Appl Toxicol 30:656-660. DOI: 10.1002/jat.1536.

Maeshima K, Yamaoka K, Kubo S, Nakano K, Iwata S, Saito K, Ohishi M, Miyahara H, Tanaka S, Ishii K, Yoshimatsu H, Tanaka Y. 2012. The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-gamma and interleukin-17 production by human CD4+ T cells. Arthritis Rheum 64:1790-1798. DOI: 10.1002/art.34329.

Muller J, Sperl B, Reindl W, Kiessling A, Berg T. 2008. Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem 9:723-727. DOI: 10.1002/cbic.200700701.