To die or not to die: a HAT trick.
ABSTRACT In this issue of Molecular Cell, two manuscripts (Sykes et al., 2006) propose that the decision to undergo apoptosis upon DNA damage is mediated through acetylation of p53 within its DNA-binding domain by MYST histone acetyltransferases.
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ABSTRACT: Compelling evidence demonstrated that melatonin increases p53 activity in cancer cells. p53 undergoes acetylation to be stabilized and activated for driving cells destined for apoptosis/growth inhibition. Over-expression of p300 induces p53 acetylation, leading to cell growth arrest by increasing p21 expression. In turn, p53 activation is mainly regulated in the nucleus by MDM2. MDM2 also acts as E3 ubiquitin ligase, promoting the proteasome-dependent p53 degradation.MDM2 entry into the nucleus is finely tuned by two different modulations: the ribosomal protein L11, acts by sequestering MDM2 in the cytosol, whereas the PI3K-AkT-dependent MDM2 phosphorylation is mandatory for MDM2 translocation across the nuclear membrane. In addition, MDM2-dependent targeting of p53 is regulated in a non-linear fashion by MDM2/MDMX interplay. Melatonin induces both cell growth inhibition and apoptosis in MCF7 breast cancer cells. We previously reported that this effect is associated to reduced MDM2 levels and increased p53 activity. Herein, we demonstrated that melatonin drastically down-regulates MDM2 gene expression and inhibits MDM2 shuttling into the nucleus, given that melatonin increases L11 and inhibits Akt-PI3K-dependent MDM2 phosphorylation. Melatonin induces a 3-fold increase in both MDMX and p300 levels, decreasing simultaneously Sirt1, a specific inhibitor of p300 activity. Consequently, melatonin-treated cells display significantly higher values of both p53 and acetylated p53. Thus, a 15-fold increase in p21 levels was observed in melatonin-treated cancer cells. Our results provide evidence that melatonin enhances p53 acetylation by modulating the MDM2/MDMX/p300 pathway, disclosing new insights for understanding its anticancer effect. This article is protected by copyright. All rights reserved.Journal of Pineal Research 06/2014; 57(1). DOI:10.1111/jpi.12150 · 7.81 Impact Factor
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ABSTRACT: This review is an update of an article published four years ago (Uversky V.N. (2009) Intrinsically disordered proteins in neurodegenerative diseases: another illustration of the D² concept. Frontiers in Bioscience 14, 5188-5238). The major goal of this review is to show the interconnections between intrinsically disordered proteins (IDPs) and human neurodegeneration. This brings to existence a new D³ concept: protein intrinsic Disorder in neuroDegenerative Diseases. An important aspect of the D³ concept is that it deals with three D³'s, emphasizing that intrinsically Disordered proteins are abundantly found in various neuroDegenerative Diseases (the first D³), that these IDPs provoke neuroDegeneration due to their Dysfunctionality (the second D³), and that neuroDegeneration-related IDPs are often controlled by other Disordered proteins (the third D³).Frontiers in Bioscience 01/2014; 19:181-258. DOI:10.2741/4204 · 4.25 Impact Factor