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Event: 2153

Key Event Title

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

Expression of factors ruling proliferation, modified

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Expression of factors ruling proliferation, modified
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
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

Organ 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

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

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
Activation of uterine estrogen receptor-alfa, endometrial adenocarcinoma KeyEvent Barbara Viviani (send email) Under development: Not open for comment. Do not cite Under Review

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
all species all species NCBI

Life Stages

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

Sex Applicability

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

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

Cell growth, division and proliferation are influenced by the action of external signals like peptide growth factors or hormones that bind and subsequently activate specific receptors. The activated receptors transmit the signal directly or indirectly, activating other substrates, to the cell nucleus.  Thus, the signals are converted into programmed responses of the cell, consisting of specific modification of gene expression (Vogt, 1993).

Proto-oncogenes have different functions, but they are all involved at different levels of signaling pathways that drive proliferation (Cline, 1987). Pro-growth proto-oncogenes might code for several proteins such as growth-factors, growth factor receptors transcription factors, signal transducers or cell cycle proteins (Cline, 1987; Robbins and Cotran, 2014). The expression of pro-growth proto-oncogenes are strictly controlled in normal cell; a disturbance of these controls may convert proto-oncogenes to oncogenes which are their constitutively activated form. Oncogenes encode oncoproteins that alter cell growth properties providing self-sufficiency in cell growth ultimately leading to oncogenic transformation (Torry & Cooper, 1991; Vogt, 1993). Proto-oncogenes that may promote cell growth when altered are the ones coding for tyrosine kinases and downstream signaling components such as RAS (Rat Sarcoma Virus), which is immediately recruited after the activation of the tyrosine kinase receptor, the downstream MAPK (mitogen-associated protein kinase) pathway and PI3K (phosphatidylinositol-3-kinase)/AKT (Protein Kinase B) pathway (Robbins and Cotran, 2014).

Growth factors: cells normally require stimulation by growth factors to proliferate. Soluble growth factors are produced by one cell type and act on a neighboring cell through a paracrine action to stimulate proliferation (Aaronson, 1991). Some cancer cells gain the ability to synthesize the same growth factor to which they are responsive, generating an autocrine loop (Shvartsman et al., 2002; Robbins and Cotran 2015). Growth factors promote entry of cells into the cell cycle, relieve blocks on cell cycle progression, prevents apoptosis, enhance the synthesis of all components are required to the formation of a new cell (Robbins and Cotran, 2014).

Transcription factors: all signal transduction pathways converge on the nucleus, where the expression of target genes involved in cell progression and mitotic cycle is activated; the consequence of altered mitogenic signaling pathways is deregulated and continuous stimulation of nuclear transcription factors that cause continue unopposed cell growth and proliferation (Baghwat & Vakoc, 2015). Hence, growth autonomy may happen because of mutations affecting the transcription factors that regulate the expression of pro-growth genes and cyclins (Robbins and Cotran, 2014).

Cyclins and Cyclin-Dependent Kinases: growth factors transduce signals that stimulate the correct progression of cells through the several phases of cell cycle which is the process by which cells replicate their DNA in preparation for cell division (Barnum & O’Connel, 2014; Wang, 2021). Progression of cells through the cell cycle is regulated by cyclin dependent kinases (CDK), which are activated by the binding to cyclins which called are called in this way due to the cyclic nature of their production and degradation. The CDK-cyclin complexes phosphorylate specific target proteins that lead cells forward through the cell cycle. There are also CDK inhibitors which role is silencing CDKs and exerting negative control over the cell cycle; the expression of these inhibitors is downregulated by several mitogenic signaling pathways, promoting the progression of the cell cycle (Barnum & O’Connel, 2014; Wang, 2021). There are two main cell cycle checkpoints one at G1 (growth phase)/S (DNA synthesis phase) transition and the other at the G2(cell growth phase)/M (mitotic phase) transition. Both cell cycle check points are tightly regulated by a balance of growth promoting and growth suppressing factors, as well as sensors of DNA damage; when activated, the DNA damage sensors cause the arrest of cell cycle progression and if the damage cannot be repaired, apoptosis is initiated. Defects in these checkpoints may lead to cancer development and progression (Shackelford et al., 1999; Robbins and Cotran, 2014).

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

Gene expression

Gene expression is directly determined by quantitating mRNA levels of the genes of interest through several established methods such as: (quantitative) real time reverse transcription polymerase chain reaction (q)RT-PCR), microarray expression profiling, whole transcriptome RNA sequencing. These two last methods allow the simultaneous quantitation of many different transcripts.

In situ hybridization localize specific RNA sequences in cells/tissues by means of complementary binding of a nucleotide probe to a specific sequence of RNA. The probes can be labeled with fluorescent- or antigen-labeled bases.

Luciferase Reporter Gene

The chemiluminescent reaction catalysed by luciferase is one of the most sensitive analytical tools for measuring gene expression identified. Because of the nature of the luciferase protein, its activity is directly measurable in in vitro translation, and in eukaryotic and prokaryotic transfection systems.

Protein expression

Protein expression can be measured in cells/tissue lysate as well as in situ. Most common methods are immunohistochemistry (in situ), western blot analysis and enzyme-linked immunosorbent assays (ELISA)

Domain of Applicability

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

All living systems, physiology and pathology.

References

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

Aaronson S. A. (1991). Growth factors and cancer. Science (New York, N.Y.), 254(5035), 1146–1153. https://doi.org/10.1126/science.1659742

Barnum, K. J., & O'Connell, M. J. (2014). Cell cycle regulation by checkpoints. Methods in molecular biology (Clifton, N.J.), 1170, 29–40. https://doi.org/10.1007/978-1-4939-0888-2_2

Bhagwat, A. S., & Vakoc, C. R. (2015). Targeting Transcription Factors in Cancer. Trends in cancer, 1(1), 53–65. https://doi.org/10.1016/j.trecan.2015.07.001

Cline M. J. (1987). The role of proto-oncogenes in human cancer: implications for diagnosis and treatment. International journal of radiation oncology, biology, physics, 13(9), 1297–1301. https://doi.org/10.1016/0360-3016(87)90219-7

Shackelford, R. E., Kaufmann, W. K., & Paules, R. S. (1999). Cell cycle control, checkpoint mechanisms, and genotoxic stress. Environmental health perspectives, 107 Suppl 1(Suppl 1), 5–24. https://doi.org/10.1289/ehp.99107s15

Shvartsman, S. Y., Hagan, M. P., Yacoub, A., Dent, P., Wiley, H. S., & Lauffenburger, D. A. (2002). Autocrine loops with positive feedback enable context-dependent cell signaling. American journal of physiology. Cell physiology, 282(3), C545–C559. https://doi.org/10.1152/ajpcell.00260.2001

Torry, D. S., & Cooper, G. M. (1991). Proto-oncogenes in development and cancer. American journal of reproductive immunology (New York, N.Y. : 1989), 25(3), 129–132. https://doi.org/10.1111/j.1600-0897.1991.tb01080.x

Vogt P. K. (1993). Cancer genes. The Western journal of medicine, 158(3), 273–278.

Wang Z. (2021). Regulation of Cell Cycle Progression by Growth Factor-Induced Cell Signaling. Cells, 10(12), 3327. https://doi.org/10.3390/cells10123327

Robbins and Cotran Pathologic Basis of Disease. 9th ed. Kumar V., Abbas A.K., Aster J.C., editors. Elsevier/Saunders; 2015. Neoplasia; pp. 284-29