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p300 and CBP are highly related histone acetyltransferase (HAT) enzymes that regulate gene expression, and their dysregulation has been linked to cancer and other diseases. p300/CBP is composed of a number of domains including a HAT domain which is inhibited by the small molecule A-485 and an acetyl-lysine binding bromodomain which was recently found to be selectively antagonized by the small molecule I-CBP112. Here we show that the combination of I-CBP112 and A-485 can synergize to inhibit prostate cancer cell proliferation. We find that the combination confers a dramatic reduction in p300 chromatin occupancy compared to the individual effects of blocking either domain alone. Accompanying this loss of p300 on chromatin, combination treatment leads to the reduction of specific mRNAs including androgen-dependent and pro-oncogenic prostate genes such as KLK3 (PSA) and c-Myc. Consistent with p300 chromatin binding directly affecting gene expression, mRNAs that are significantly reduced by combination treatment also exhibit a strong reduction in p300 chromatin occupancy at their gene promoters. The relatively few mRNAs that are up-regulated upon combination treatment show no correlation with p300 occupancy. These studies provide support for the pharmacologic advantage of concurrent targeting of two domains within one key epigenetic modification enzyme.
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The transcriptional co-activator p300 is essential for p53 transactivation, although its precise role remains unclear. We report that p53 activates the acetyltransferase activity of p300 through the e...
Herein we report the discovery of a series of new PCAF bromodomain (BRD) inhibitors, which were obtained through a hit discovery process and subsequent structure-based optimization and structure-activ...
In the present study, a screen of adenosine analogs as potential modulators of arylamine-N-acetyltransferase 1 activity identified ATP as an inhibitor within its range of physiological concentrations....
The bromodomain and extra terminal (BET) family of bromodomain containing proteins (BCPs) have been the subject of extensive research over the past decade, resulting in a plethora of high quality chem...
Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (C...
Patients with Amyotrophic Lateral Sclerosis (ALS) will use a P300 based brain computer interface (BCI) keyboard to type in assistive technology devices. The results of this study will be ...
Bilateral severe to profound hearing loss is a socially disabling handicap. Cochlear implants can be used to improve hearing in cases where conventional hearing aids are not effective. The...
The Evidence Amyloid Study EEG (EASE) establishes an open-label, longitudinal cohort study to measure of neurological functioning during the onset and progression of cognitive decline in p...
This is a single site study to determine the structural efficacy of sarilumab when administered to biologic naive patients with active rheumatoid arthritis
This is a controlled trial designed to determine short- and long-term effects of repeated tDCS on the P300 component of event-related evoked potentials in patients with chronic neuropathi...
A member of the p300-CBP transcription factors that was originally identified as a binding partner for ADENOVIRUS E1A PROTEINS.
An enzyme that catalyzes the transfer of acetyl groups from ACETYL-COA to arylamines. It can also catalyze acetyl transfer between arylamines without COENZYME A and has a wide specificity for aromatic amines, including SEROTONIN. However, arylamine N-acetyltransferase should not be confused with the enzyme ARYLALKYLAMINE N-ACETYLTRANSFERASE which is also referred to as SEROTONIN ACETYLTRANSFERASE.
An acetyltransferase with specificity towards the amine group of aromatic alkylamines (arylalkylamines) such as SEROTONIN. This enzyme is also referred to as serotonin acetylase despite the fact that serotonin acetylation can also occur through the action of broad specificity acetyltransferases such as ARYLAMINE N-ACETYLTRANSFERASE.
A retinoblastoma-binding protein that is found as a subunit of protein complexes involved in the acetylation of newly synthesized histones. Although initially discovered as a retinoblastoma binding protein, it also has an affinity for core HISTONES and plays a role in recruiting core histone proteins to the active site of the acetyltransferase enzyme complexes.
A late-appearing component of the event-related potential. P300 stands for a positive deflection in the event-related voltage potential at 300 millisecond poststimulus. Its amplitude increases with unpredictable, unlikely, or highly significant stimuli and thereby constitutes an index of mental activity. (From Campbell, Psychiatric Dictionary, 6th ed)
The process of gene expression is used by eukaryotes, prokaryotes, and viruses to generate the macromolecular machinery for life. Steps in the gene expression process may be modulated, including the transcription, RNA splicing, translation, and post-tran...
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