API

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Relationship: 3562

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

SIX1 gene expression, increased leads to SIX1 protein expression, increased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
SIX1 gene expression, increased
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
SIX1 protein expression, increased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Early-life estrogen receptor agonism leading to endometrial adenosquamous carcinoma via promotion of sine oculis homeobox 1 progenitor cells adjacent High Not Specified Travis Karschnik (send email) Under Development: Contributions and Comments Welcome

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Vertebrates Vertebrates NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Female High
Unspecific

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Not Otherwise Specified
Adult, reproductively mature High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Sine oculis homeobox 1 (SIX1) gene expression leads to Sine oculis homeobox 1 protein expression via standard cellular transcription and translation processes.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This Key Event Relationship was part of an Environmental Protection Agency effort to develop AOPs that establish scientifically supported causal linkages between alternative endpoints measured using new approach methodologies (NAMs) and guideline apical endpoints measured in Tier 1 and Tier 2 test guidelines (U.S. EPA, 2024) employed by the Endocrine Disruptor Screening Program (EDSP).  A series of key events that represent significant, measurable, milestones connecting molecular initiation to apical endpoints indicative of adversity were identified based on scientific review articles and empirical studies.  Additionally, scientific evidence supporting the causal relationships between each pair of key events was assembled and evaluated.  The present effort focused primarily on empirical studies with laboratory rodents and other mammals.

Xin, Li, & Yang 2016 was used as an originating publication followed by further investigation of the bibliography and google scholar to retrieve full articles. 

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Transcription and translation processes, which are foundational to virtually all protein-coding genes, apply to SIX1. 

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

In the case of Xin, Li, & Yang 2016, western blots and RT-qPCR were conducted 48 hours after transfection.  The transcription and translation process, generally, has been shown to take anywhere from a minute to several hours to reach a functional protein.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic Applicability

The empirical evidence presented here is limited to human endometrial cell lines.  However, given fundamental transcription and translation principles, it could be reasonably concluded that SIX1 gene expression would result in SIX1 protein expression in all species where SIX1 is present.

Lifestage Applicability

The endometrial cell lines presented in the empirical evidence originated from 39 (Ishikawa) and 71-year-old (HEC1B) female patients.  Again, given fundamental transcription and translation principles, it could be reasonably concluded that SIX1 gene expression would result in SIX1 protein expression in all lifestages where SIX1 is present.

Sex Applicability

The empirical evidence presented here is limited to female patients.  SIX1 is not sex-restricted however, so this relationship could be expected to occur in any sex.

References

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

Xin, X., Li, Y., & Yang, X. (2016). SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling. Oncology letters, 12(5), 3435-3440.