![]() reported a naturally occurring HAT inhibitor, anacardic acid, from cashew nut shell liquid. ![]() On the other hand, inhibitors of the class of MYST HATs are rarely reported. Most of the developed inhibitors target robust HATs p300/CBP and PCAF/GCN5. In light of the significance of HAT inhibitors as potential new therapeutics, quite a few efforts have been invested on developing small molecule inhibitors of HAT enzymes. These observations highlight the significance of Tip60 as a potential pharmacological target in disease therapy. Therefore, upregulation of Tip60 may provide a mechanistic explanation why androgen receptor-regulated genes become expressed when the tumor relapses. Importantly, in hormone resistant prostate cancer cells, Tip60 is constitutively recruited to androgen response elements such as prostate-specific antigen (PSA) promoter and enhances PSA expression even in the absence of androgen. Tip60 is upregulated and predominantly resides in the nucleus of hormone resistant prostate cancer cells and tissue specimens from patients who failed endocrine therapy. In prostate cancer, Tip60 is particularly involved in the progression to the androgen-refractory state. The protein level of Tip60 is substantially high and contributes to the abnormal HAT activity in ODC/Ras tumors. Oncogenic transcription factors including c-Myc, E2F, and nuclear factor-κB associate with and are coactivated by Tip60. Research has shown that Tip60 is intimately linked to oncogenesis. In the pathogenesis of Alzheimer’s disease, the intracellular C-terminal part of β-amyloid precursor protein (APP) associates with the APP-binding protein Fe65 and Tip60, leading to apoptosis and downstream gene activation in parallel with the pathway of the amyloid β-peptide release. Tip60 is recruited by many key transcription factors to the chromatin template and aberrant Tip60 activity is involved in several types of human diseases such as neurodegeneration and cancer. ![]() The acetylation of histones results in charge neutralization of lysine residues and decreases the affinity between histones and nucleic acids, and leads to relaxed open chromatin structures. It catalyzes the transfer of acetyl groups from acetyl-CoA to specific lysine residues on the N-terminal tail of nucleosomal core histones. The 60-kDa HIV Tat-interacting protein (Tip60), one of the founding members of the MYST (MOZ, Ybf2/Sas3, Sas2, Tip60) family of histone acetyltransferases (HATs), was originally identified as an HIV-1 Tat associating protein by yeast two-hybrid screen. ![]()
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