Ubiquitylation and Cancer Molecular Biology Laboratory, Inbiomed, Mikeletegi 81, San Sebastián-Donostia 20009, Gipuzkoa, Spain. Electronic address:
Published: July 2014
AI Article Synopsis
Article Abstract
The tumor suppressor p53 regulates the expression of genes involved in cell cycle progression, senescence and apoptosis. Here, we investigated the effect of single point mutations in the oligomerization domain (OD) on tetramerization, transcription, ubiquitylation and stability of p53. As predicted by docking and molecular dynamics simulations, p53 OD mutants show functional defects on transcription, Mdm2-dependent ubiquitylation and 26S proteasome-mediated degradation. However, mutants unable to form tetramers are well degraded by the 20S proteasome. Unexpectedly, despite the lower structural stability compared to WT p53, p53 OD mutants form heterotetramers with WT p53 when expressed transiently or stably in cells wild type or null for p53. In consequence, p53 OD mutants interfere with the capacity of WT p53 tetramers to be properly ubiquitylated and result in changes of p53-dependent protein expression patterns, including the pro-apoptotic proteins Bax and PUMA under basal and adriamycin-induced conditions. Importantly, the patient derived p53 OD mutant L330R (OD1) showed the more severe changes in p53-dependent gene expression. Thus, in addition to the well-known effects on p53 stability, ubiquitylation defects promote changes in p53-dependent gene expression with implications on some of its functions.
Background: Doxorubicin-induced cardiotoxicity is still an important medical problem associated with a high mortality rate in cancer survivors. p53 plays a key role in doxorubicin-induced cardiotoxicity. Diacylglycerol kinase ζ (Dgkζ), a 130-kDa enzyme abundant in cardiomyocytes, regulates the p53 protein expression level in neurons.
Pharmacological reactivation of the tumor suppressor p53 remains a key challenge for the treatment of cancer. Acetylation Targeting Chimera (AceTAC), a novel technology is previously reported that hijacks lysine acetyltransferases p300/CBP to acetylate the p53Y220C mutant. However, p300/CBP are the only acetyltransferases harnessed for AceTAC development to date.
Hainan Pharmaceutical Research and Development Science Park, Hainan Academy of Medical Sciences, Hainan Medical University, No. 3 Xueyuan Road, Haikou 571199, China.
Two new quinazolinone nitriles (1 and 2) and one new indole alkaloid (3), together with 13 known compounds, were isolated from the deep-sea-derived MCCC 3A00265. Their structures were determined by extensive spectroscopic analysis, with the absolute configurations established by comparing experimental and calculated electronic circular dichroism (ECD) and optical rotation (OR) data as well as biogenetic considerations. Viricyanoamides A and B (1 and 2) are the sole representatives of quinazolinones featuring a nitrile group, while solitumidine F (3) incorporates a rare pyrrolidinedione unit as an indole terpenoid.
The Human papillomaviruses (HPV) have existed in the human population since the archaic hominids. Over the course of human migration and evolution, HPVs have co-evolved with humans on all continents to become today the leading cause of cervical cancer. HPVs are classified by genera, species, genotype, lineage, sub-lineage and variants.
The mesenchymal transformations of infiltrating gliomas are uncommon events. This is particularly true of IDH-mutant astrocytomas and oligodendrogliomas, in which mesenchymal transformation is exceedingly rare. oligosarcoma is a newly recognized methylation class (MC) that represents transformed 1p/19q co-deleted oligodendrogliomas, but recent studies indicate it may be non-specific.
