The Identification of a Novel Natural Activator of p300 Histone Acetyltranferase Provides New Insights into the Modulation Mechanism of this Enzyme

Piaz, Fabrizio Dal; Tosco, Alessandra; Eletto, Daniela; Piccinelli, Anna Lisa; Moltedo, Ornella; Franceschelli, Silvia; Sbardella, Gianluca; Remondelli, Paolo; Rastrelli, Luca; Vesci, Loredana; Pisano, Claudio; Tommasi, Nunziatina De

doi:10.1002/cbic.200900721

Cited by 65 publications

(31 citation statements)

References 42 publications

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“…SPR analyses were carried out according to our previously published procedures [22], [23]. Briefly, SPR analyses were performed using a Biacore 3000 optical biosensor equipped with research−grade CM5 sensor chips (GE Healthcare).…”

Section: Methodsmentioning

confidence: 99%

Identification of the Plant Compound Geraniin as a Novel Hsp90 Inhibitor

et al. 2013

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Besides its function in normal cellular growth, the molecular chaperone heat shock protein 90 (Hsp90) binds to a large number of client proteins required for promoting cancer cell growth and/or survival. In an effort to discover new small molecules able to inhibit the Hsp90 ATPase and chaperoning activities, we screened, by a surface plasmon resonance assay, a small library including different plant polyphenols. The ellagitannin geraniin, was identified as the most promising molecule, showing a binding affinity to Hsp90α similar to that of 17-(allylamino)-17-demethoxygeldanamycin (17AGG). Geraniin was able to inhibit in vitro the Hsp90α ATPase activity in a dose−dependent manner, with an inhibitory efficiency comparable to that measured for 17-AAG. In addition, this compound compromised the chaperone activity of Hsp90α, monitored by the citrate synthase thermal induced aggregation assay. Geraniin decreased the viability of HeLa and Jurkat cell lines and caused an arrest in G2/M phase. We also proved that following exposure to different concentrations of geraniin, the level of expression of the client proteins c-Raf, pAkt, and EGFR was strongly down−regulated in both the cell lines. These results, along with the finding that geraniin did not exert any appreciable cytotoxicity on normal cells, encourage further studies on this compound as a promising chemical scaffold for the design of new Hsp90 inhibitors.

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Section: Methodsmentioning

confidence: 99%

Identification of the Plant Compound Geraniin as a Novel Hsp90 Inhibitor

et al. 2013

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“…Thermodynamic studies using surface plasmon resonance indicated that nemorosone has high affinity towards p300 protein (0.25 μM), and this interaction is associated with a low kinetic dissociation constant (3.2×10 -4 s -1 ), suggesting a hardly dissociable complex with a stable tertiary structure. Furthermore, the major region of nemorosone, which interacts with p300, was identified as a hydroxylated enol involving C(2), C(3), and C(4) [73]. Efforts to isolate small-molecule activators using the basic backbone structure of anacardic acid are currently underway.…”

Section: Druggability Of Hat Domainsmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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“…Several mechanisms have been proposed to account for this action, including its ability to target the Akt/PKB signal transducer (Díaz-Carballo et al, 2008a,b) and to induce p300 histone acetyltransferase (Dal Piaz et al, 2010). Here, we provide for the first time evidence that, in addition to its toxicity on HepG2 cells, nemorosone is a potent protonophoric mitochondrial uncoupler.…”

Section: Discussionmentioning

confidence: 70%