Epigenetic control of KRAS-induced transformation by GLI transcription factors

Pancreatology ◽  
2013 ◽  
Vol 13 (2) ◽  
pp. e25
Author(s):  
M.G. Fernandez-Barrena ◽  
L.L. Almada ◽  
M.E. Fernandez-Zapico
Keyword(s):  
Transcription Factors ◽  
Epigenetic Control ◽  
Gli Transcription Factors

Pirfenidone exerts anti-fibrotic effects through Inhibition of GLI transcription factors

Pneumologie ◽  
2018 ◽  
Vol 72 (S 01) ◽  
pp. S114-S115
Author(s):  
M Wygrecka ◽  
M Didiasova ◽  
R Singh ◽  
J Wilhelm ◽  
G Kwapiszewska ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gli Transcription Factors

scholarly journals Fuzzy modeling reveals a dynamic self-sustaining network of the GLI transcription factors controlling important metabolic regulators in adult mouse hepatocytes

2015 ◽  
Vol 11 (8) ◽  
pp. 2190-2197 ◽  
Author(s):  
Wolfgang Schmidt-Heck ◽  
Madlen Matz-Soja ◽  
Susanne Aleithe ◽  
Eugenia Marbach ◽  
Reinhard Guthke ◽  
...  
Keyword(s):  
Fuzzy Logic ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Adult Mouse ◽  
Dynamic Features ◽  
Hedgehog Signalling ◽  
Gli Transcription Factors ◽  
Mouse Hepatocytes ◽  
Metabolic Regulators ◽  
Modelling Approach

The Hedgehog signalling-driven Gli transcription factors in hepatocytes form a regulatory network identified by a fuzzy-logic modelling approach. The network explains dynamic features important for hepatocyte function and fate.

Hedgehog-induced ciliary trafficking of kinesin-4 motor KIF7 requires intraflagellar transport but not KIF7’s microtubule binding

2021 ◽  
Author(s):  
Yang Yue ◽  
Martin F. Engelke ◽  
T. Lynne Blasius ◽  
Kristen J. Verhey
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Primary Cilium ◽  
Hedgehog Signaling ◽  
Intraflagellar Transport ◽  
Hedgehog Signaling Pathway ◽  
Microtubule Binding ◽  
Pathway Activation ◽  
Gli Transcription Factors ◽  
Ciliary Localization

The kinesin-4 motor KIF7 is a conserved regulator of the Hedgehog signaling pathway. In vertebrates, Hedgehog signaling requires the primary cilium, and KIF7 and Gli transcription factors accumulate at the cilium tip in response to Hedgehog activation. Unlike conventional kinesins, KIF7 is an immotile kinesin and its mechanism of ciliary accumulation is unknown. We generated KIF7 variants with altered microtubule binding or motility. We demonstrate that microtubule binding of KIF7 is not required for the increase in KIF7 or Gli localization at the cilium tip in response to Hedgehog signaling. In addition, we show that the immotile behavior of KIF7 is required to prevent ciliary localization of Gli transcription factors in the absence of Hedgehog signaling. Using an engineered kinesin-2 motor that enables acute inhibition of intraflagellar transport (IFT), we demonstrate that kinesin-2 KIF3A/KIF3B/KAP mediates the translocation of KIF7 to the cilium tip in response to Hedgehog pathway activation. Together, these results suggest that KIF7’s role at the tip of the cilium is unrelated to its ability to bind to microtubules.

scholarly journals Gli Transcription Factors Mediate the Oncogenic Transformation of Prostate Basal Cells Induced by a Kras-Androgen Receptor Axis

2016 ◽  
Vol 291 (49) ◽  
pp. 25749-25760 ◽  
Author(s):  
Meng Wu ◽  
Lishann Ingram ◽  
Ezequiel J. Tolosa ◽  
Renzo E. Vera ◽  
Qianjin Li ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Androgen Receptor ◽  
Basal Cells ◽  
Oncogenic Transformation ◽  
Gli Transcription Factors

scholarly journals Computational Prediction and Experimental Verification of New MAP Kinase Docking Sites and Substrates Including Gli Transcription Factors

2010 ◽  
Vol 6 (8) ◽  
pp. e1000908 ◽  
Author(s):  
Thomas C. Whisenant ◽  
David T. Ho ◽  
Ryan W. Benz ◽  
Jeffrey S. Rogers ◽  
Robyn M. Kaake ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Map Kinase ◽  
Experimental Verification ◽  
Computational Prediction ◽  
Gli Transcription Factors ◽  
Docking Sites

scholarly journals Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia

2021 ◽  
Vol 22 (19) ◽  
pp. 10670
Author(s):  
Fabian Freisleben ◽  
Franziska Modemann ◽  
Jana Muschhammer ◽  
Hauke Stamm ◽  
Franziska Brauneck ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Chemotherapy Resistance ◽  
Proteasomal Degradation ◽  
Antitumor Effects ◽  
Binding Interaction ◽  
Atp Binding Site ◽  
Protein Levels ◽  
Gli Transcription Factors ◽  
Reporter Assays ◽  
Dynamics Simulations

The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.

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