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Event: 2330

Key Event Title

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

Sine oculis homeobox 1 protein expression, increased

Short name

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SIX1 protein expression, increased

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Biological Context

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Level of Biological Organization
Molecular

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
precursor cell

Organ term

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
translation	homeobox protein SIX1	increased

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
Early-life ER agonism and endometrial adenosquamous carcinoma via SIX1 expression	KeyEvent	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 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 musculus	Mus musculus	High	NCBI
Gallus gallus	Gallus gallus	High	NCBI

Life Stages

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

Life stage	Evidence
Embryo	High
Fetal	High
Adult	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

The sine oculis homeobox homolog (SIX1) protein is a transcription factor whose expression varies widely throughout an organisms lifespan. It plays a central role during during embryonic development; contributing to skeletal myogensis, sensory neuron develpment, nephrogenisis, and mammary gland development, among others (Coletta et al., 2010, O'Brien et al., 2016, Yajima et al., 2014, and Wu et al., 2014). In normal adults, SIX1 levels are greatly reduced but can be re-activated in response to injury and some forms of cancer (Jin et al., 2021). It has also been shown to be a novel repressor of senescence (Adrados et al., 2016).

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

Detection and quantification methods include:

Western blotting
Immunohistochemistry
Immunofluorescence
Flow cytometry
ELISA

Domain of Applicability

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

Taxonomic Applicability

Measurements of SIX1 protein levels have been made across vertebrates, mice, fish, amphibians and humans. Though conserved, there are different regulatory mechanisms across species and organ progenitor cells (O'Brien et al., 2016). SeqAPASS results for taxonomic conservation is attached for SIX1a (NP_001009904.1), SIX1b (NP_996978.1), and SIX1 (NP_005973.1) as SIX1 SeqAPASS.csv.

Lifestage Applicability

It is expressed most highly early in development but can be re-expressed in response to injury and as assocatied with cancer.

Sex Applicability

Expression of this protein is not sex specific.

References

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

Adrados, I., Larrasa-Alonso, J., Galarreta, A., López-Antona, I., Menéndez, C., Abad, M., ... & Palmero, I. (2016). The homeoprotein SIX1 controls cellular senescence through the regulation of p16INK4A and differentiation-related genes. Oncogene, 35(27), 3485-3494.

Coletta, R. D., McCoy, E. L., Burns, V., Kawakami, K., McManaman, J. L., Wysolmerski, J. J., & Ford, H. L. (2010). Characterization of the Six1 homeobox gene in normal mammary gland morphogenesis. BMC developmental biology, 10(1), 4.

Jin, Y., Zhang, M., Li, M., Zhang, H., Zhao, L., Qian, C., ... & Cao, C. (2021). SIX1 activation is involved in cell proliferation, migration, and anti-inflammation of acute ischemia/reperfusion injury in mice. Frontiers in Molecular Biosciences, 8, 725319.

Ma, M., Cai, B., Jiang, L., Abdalla, B. A., Li, Z., Nie, Q., & Zhang, X. (2018). lncRNA-Six1 is a target of miR-1611 that functions as a ceRNA to regulate Six1 protein expression and fiber type switching in chicken myogenesis. Cells, 7(12), 243.

McCoy, E. L., Iwanaga, R., Jedlicka, P., Abbey, N. S., Chodosh, L. A., Heichman, K. A., ... & Ford, H. L. (2009). Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial-mesenchymal transition. The Journal of clinical investigation, 119(9), 2663-2677.

Micalizzi, D. S., Christensen, K. L., Jedlicka, P., Coletta, R. D., Barón, A. E., Harrell, J. C., ... & Ford, H. L. (2009). The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-β signaling. The Journal of clinical investigation, 119(9), 2678-2690.

O'Brien, L. L., Guo, Q., Lee, Y., Tran, T., Benazet, J. D., Whitney, P. H., ... & McMahon, A. P. (2016). Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators. Development, 143(4), 595-608.

Wu, W., Huang, R., Wu, Q., Li, P., Chen, J., Li, B., & Liu, H. (2014). The role of Six1 in the genesis of muscle cell and skeletal muscle development. International journal of biological sciences, 10(9), 983.

Yajima, H., Suzuki, M., Ochi, H., Ikeda, K., Sato, S., Yamamura, K. I., ... & Kawakami, K. (2014). Six1 is a key regulator of the developmental and evolutionary architecture of sensory neurons in craniates. BMC biology, 12(1), 40.