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Event: 2028

Key Event Title

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

Decrease, GLI1/2 translocation to nucleus

Short name

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Decrease, GLI1/2 translocation

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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
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
protein import into nucleus, translocation	zinc finger protein GLI1	decreased
protein import into nucleus, translocation	zinc finger protein GLI2	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
Anatagonsim SMO leads to OFC	KeyEvent	Jacob Reynolds (send email)	Under development: Not open for comment. Do not cite

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

Life Stages

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

Life stage	Evidence
Embryo	High
All life stages	High

Sex Applicability

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

Term	Evidence
Unspecific

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 Glioma-associated onocogene (Gli) family of zinc finger transcription factors (Gli1, Gli2, Gli3) are the primarily downstream effectors of the Hedgehog (HH) signaling cascade. When HH ligand binds to Patched (PTCH), its’ inhibition on SMO is relieved. SMO this then able to accumulate to the tip of primary cilium in its’ active form (Corbit, Aanstad et al. 2005, Rohatgi, Milenkovic et al. 2007, Kim, Kato et al. 2009). SMO causes the GLI family to become dislodged from their complex with the negative regulator of HH signaling, Suppressor of Fused (Sufu) (Kogerman, Grimm et al. 1999, Pearse, Collier et al. 1999, Stone, Murone et al. 1999, Tukachinsky, Lopez et al. 2010). The GLI-Sufu complex maintains retention of Gli in the cytosol allowing for exposure to phosphorylation via protein kinase A (PKA) which inhibits downstream signal transduction (Tuson, He et al. 2011). When SMO is activated the GLI2/3-Sufu complex is dismantled allowing for retrograde transport of GLI back into the nucleus (Kim, Kato et al. 2009).

The GLI family is found in both a long activator form (GliA) or a proteolytically cleaved repressor form (GliR). Current understanding is that Gli3 functions primarily as a repressor while Gli1 and Gli2 function mainly as activators of the pathway and that recruitment of SMO to the cilium leads to a increase in the ratio of GliA:GliR (Hui and Angers 2011, Liu 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

A nuclear translocation assay (NTA) can be applied to determine the amount of protein that translocate into the nucleus (Dixon and Lim 2010).
Nuclear protein extracts can be analysed to determine if the protein of interest (GLI1/2) translocated to the nucleus (Kim, Kato et al. 2009).
Immunofluorescence and microscopy can be used to determine how much of a protein has translocated to the nucleus. Primary antibodies can be used to tag GLI in combination with a secondary stain for the nucleus (Blotta, Jakubikova et al. 2012).

Domain of Applicability

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

Sex- The Gli family of transcription factors is present in both male and females and differences in activation or antagonism between sex have not been demonstrated.
Life stages- The Hedgehog pathway is a major pathway in embryonic development. Aberrant activation of HH signalling is known to cause cancer (Dahmane, Lee et al. 1997, Kimura, Stephen et al. 2005). For these reasons all stages of life are of relevance.
Taxonomic-HH signalling including the Gli transcription factors is present in vertebrates and some invertebrates inclubind flies (Denef, Neubüser et al. 2000, Huangfu and Anderson 2005)

References

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

Blotta, S., J. Jakubikova, T. Calimeri, A. M. Roccaro, N. Amodio, A. K. Azab, U. Foresta, C. S. Mitsiades, M. Rossi, K. Todoerti, S. Molica, F. Morabito, A. Neri, P. Tagliaferri, P. Tassone, K. C. Anderson and N. C. Munshi (2012). "Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma." Blood 120(25): 5002-5013.

Corbit, K. C., P. Aanstad, V. Singla, A. R. Norman, D. Y. R. Stainier and J. F. Reiter (2005). "Vertebrate Smoothened functions at the primary cilium." Nature 437(7061): 1018-1021.

Dahmane, N., J. Lee, P. Robins, P. Heller and A. Ruiz i Altaba (1997). "Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours." Nature 389(6653): 876-881.

Denef, N., D. Neubüser, L. Perez and S. M. Cohen (2000). "Hedgehog induces opposite changes in turnover and subcellular localization of patched and smoothened." Cell 102(4): 521-531.

Dixon, A. S. and C. S. Lim (2010). "The nuclear translocation assay for intracellular protein-protein interactions and its application to the Bcr coiled-coil domain." Biotechniques 49(1): 519-524.

Huangfu, D. and K. V. Anderson (2005). "Cilia and Hedgehog responsiveness in the mouse." Proc Natl Acad Sci U S A 102(32): 11325-11330.

Hui, C. C. and S. Angers (2011). "Gli proteins in development and disease." Annu Rev Cell Dev Biol 27: 513-537.

Kim, J., M. Kato and P. A. Beachy (2009). "Gli2 trafficking links Hedgehog-dependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus." Proc Natl Acad Sci U S A 106(51): 21666-21671.

Kimura, H., D. Stephen, A. Joyner and T. Curran (2005). "Gli1 is important for medulloblastoma formation in Ptc1+/- mice." Oncogene 24(25): 4026-4036.

Kogerman, P., T. Grimm, L. Kogerman, D. Krause, A. B. Undén, B. Sandstedt, R. Toftgård and P. G. Zaphiropoulos (1999). "Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1." Nat Cell Biol 1(5): 312-319.

Liu, K. J. (2016). "Craniofacial Ciliopathies and the Interpretation of Hedgehog Signal Transduction." PLoS Genet 12(12): e1006460.

Pearse, R. V., 2nd, L. S. Collier, M. P. Scott and C. J. Tabin (1999). "Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators." Dev Biol 212(2): 323-336.

Rohatgi, R., L. Milenkovic and M. P. Scott (2007). "Patched1 regulates hedgehog signaling at the primary cilium." Science 317(5836): 372-376.

Stone, D. M., M. Murone, S. Luoh, W. Ye, M. P. Armanini, A. Gurney, H. Phillips, J. Brush, A. Goddard, F. J. de Sauvage and A. Rosenthal (1999). "Characterization of the human suppressor of fused, a negative regulator of the zinc-finger transcription factor Gli." J Cell Sci 112 ( Pt 23): 4437-4448.

Tukachinsky, H., L. V. Lopez and A. Salic (2010). "A mechanism for vertebrate Hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes." J Cell Biol 191(2): 415-428.

Tuson, M., M. He and K. V. Anderson (2011). "Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube." Development 138(22): 4921-4930.