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Key Event Title
Decrease, GLI1/2 translocation to nucleus
|Level of Biological Organization|
Key Event Components
|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
|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 Do not cite|
|All life stages||High|
Key Event Description
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 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
- 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)
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.