2013
DOI: 10.1371/journal.pone.0065718
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Gli2 Acetylation at Lysine 757 Regulates Hedgehog-Dependent Transcriptional Output by Preventing Its Promoter Occupancy

Abstract: The morphogenic Hedgehog (Hh) signaling regulates postnatal cerebellar development and its aberrant activation leads to medulloblastoma. The transcription factors Gli1 and Gli2 are the activators of Hh pathway and their function is finely controlled by different covalent modifications, such as phosphorylation and ubiquitination. We show here that Gli2 is endogenously acetylated and that this modification represents a key regulatory step for Hedgehog signaling. The histone acetyltransferase (HAT) coactivator p3… Show more

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Cited by 62 publications
(72 citation statements)
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“…We recently identified overexpression of aPKC as a powerful mechanism of drug resistance in advanced BCCs Tables 5 and 6). This observation, coupled with previous data demonstrating that inhibition of aPKC (23) or HDAC1 (8,11) results in an abolishment of GLI1's chromatin affinity, as assayed by ChIP without perturbing its nuclear-cytoplasmic trafficking, led us to the hypothesis that aPKC and HDAC1 work in concert to modulate GLI1's transcriptional status.…”
Section: Drug Repositioning Identifies Vorinostat For Bcc Treatmentmentioning
confidence: 70%
See 1 more Smart Citation
“…We recently identified overexpression of aPKC as a powerful mechanism of drug resistance in advanced BCCs Tables 5 and 6). This observation, coupled with previous data demonstrating that inhibition of aPKC (23) or HDAC1 (8,11) results in an abolishment of GLI1's chromatin affinity, as assayed by ChIP without perturbing its nuclear-cytoplasmic trafficking, led us to the hypothesis that aPKC and HDAC1 work in concert to modulate GLI1's transcriptional status.…”
Section: Drug Repositioning Identifies Vorinostat For Bcc Treatmentmentioning
confidence: 70%
“…HDAC1 is itself a transcriptional target of GLI, creating a third positive feedback loop of HH signaling. Of particular interest, HDAC inhibition has been proposed for the treatment of many HH-driven cancers (8)(9)(10)(11). HDAC inhibitors block growth and promote apoptosis by altering the histone-DNA complex and by altering the acetylation status of nonhistone proteins (12).…”
Section: Introductionmentioning
confidence: 99%
“…Furthermore, Y859, Y872 and S1060 of Gli1 are cooperatively bound by the E3 ligase Itch (Di Marcotullio et al, 2006a, while D C degrons (residues 462-467) bind bTrCP, all leading to protein ubiquitination and degradation (Huntzicker et al, 2006). Finally, K518 (Gli1) and K757 (Gli2) are instead acetylatable residues preventing transcriptional activity Coni et al, 2013b), whereas T374 of the Gli1ZF is a major PKA site contrasting Gli1 localization into the nucleus (Sheng et al, 2006). Once phosphorylated by aPKCι/k, S243 and T304 of the GliZF confer to the protein an enhanced ability to form a complex with DNA (Atwood et al, 2013), possibly through a conformational change or binding stabilization or the recruitment of additional co-regulatory proteins, as these amino acids are located in ZF-1 and ZF-3 that mainly establish a few contacts only with the phosphate backbone.…”
Section: Molecular Bases Of Gli1/dna Interactionmentioning
confidence: 99%
“…30,31 Cell pellets were lysed in TRI reagent solution (Ambion) and total RNA was purified. cDNA was synthesized using SuperScript II Reverse Transcriptase (Invitrogen) and transcript levels were quantified on an Applied Biosystems ViiA 7 Real-Time PCR System instrument using Power Sybr Green PCR Master Mix (Applied Biosystems).…”
Section: Medulloblastoma Allograft Modelmentioning
confidence: 99%
“…31 The following antibodies and conditions were used: Ki67 (1:200, Leica Biosystems) was diluted in 1% serum PBS-T. Caspase 3 (1:500, Cell Signaling) was diluted in 5% serum PBS-T. Antibodies were incubated for one hour at room temperature. Nuclei were counterstained with hematoxylin in accordance with standard procedures.…”
Section: Immunohistochemistrymentioning
confidence: 99%