Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
p53 is a tumour suppressor that regulates the cellular response to genotoxic stresses. p53 is a short-lived protein and its activity is regulated mostly by stabilization via different post-translational modifications. Here we report a novel mechanism of p53 regulation through lysine methylation by Set9 methyltransferase. Set9 specifically methylates p53 at one residue within the carboxyl-terminus regulatory region. Methylated p53 is restricted to the nucleus and the modification positively affects its stability. Set9 regulates the expression of p53 target genes in a manner dependent on the p53-methylation site. The crystal structure of a ternary complex of Set9 with a p53 peptide and the cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular basis for recognition of p53 by this lysine methyltransferase.
We have identi®ed a novel protein, BAP1, which binds to the RING ®nger domain of the Breast/Ovarian Cancer Susceptibility Gene product, BRCA1. BAP1 is a nuclearlocalized, ubiquitin carboxy-terminal hydrolase, suggesting that deubiquitinating enzymes may play a role in BRCA1 function. BAP1 binds to the wild-type BRCA1-RING ®nger, but not to germline mutants of the BRCA1-RING ®nger found in breast cancer kindreds. BAP1 and BRCA1 are temporally and spatially coexpressed during murine breast development and remodeling, and show overlapping patterns of subnuclear distribution. BAP1 resides on human chromosome 3p21.3; intragenic homozgyous rearrangements and deletions of BAP1 have been found in lung carcinoma cell lines. BAP1 enhances BRCA1-mediated inhibition of breast cancer cell growth and is the ®rst nuclearlocalized ubiquitin carboxy-terminal hydrolase to be identi®ed. BAP1 may be a new tumor suppressor gene which functions in the BRCA1 growth control pathway.
Cellular DNA damage causes stabilization and activation of the tumor suppressor and transcription factor p53, in part by promoting multiple covalent modifications of the p53 protein, including acetylation. We investigated the importance of acetylation in p53 function and the mechanism by which acetylation influences p53 activity. Acetylation site substitutions reduced p53-dependent transcriptional induction and G1 cell cycle arrest. Chromatin immunoprecipitation analysis of the endogenous p21 promoter showed increased association of p53, coactivators (CBP and TRRAP), and acetylated histones following cell irradiation. Results with acetylation-defective p53 demonstrate that the critical function of acetylation is not to increase the DNA binding affinity of p53 but rather to promote coactivator recruitment and histone acetylation. Therefore, we propose that an acetylation cascade consisting of p53 acetylation-dependent recruitment of coactivators/HATs is crucial for p53 function.
Many transcription coactivators interact with nuclear receptors in a ligandThe nuclear receptor superfamily is a group of proteins that regulate, in a ligand-dependent manner, transcriptional initiation of target genes by binding to specific DNA sequences named hormone response elements (reviewed in reference 23). Functional analysis of nuclear receptors has shown that there are two major activation domains. The N-terminal domain (AF1) contains a ligand-independent activation function, whereas the ligand-binding domain (LBD) exhibits ligand-dependent transactivation function (AF2). The AF2 core region, located at the extreme C terminus of the receptor LBDs, is conserved among nuclear receptors and undergoes a major conformational change upon ligand binding (23). This region has been shown to play a critical role in mediating transactivation by serving as a ligand-dependent interaction interface with many different coactivators (reviewed in reference 9). These coactivators, including the p160 family members (i.e., SRC-1, SRC-2/GRIP1/TIF2, and SRC-3/ACTR/pCIP/AIB1/ RAC3/TRAM1), CBP/p300, p/CAF, TRAP/DRIP, activating signal cointegrator 2 (ASC-2), and many others, bridge nuclear receptors and the basal transcription apparatus and/or remodel the chromatin structures (9).Chromatin, the physiological template of all eukaryotic genetic information, undergoes a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA (reviewed in reference 12). SRC-1 and the p160 family member ACTR, along with CBP and p300, were recently shown to contain histone acetyltransferase (HAT) activities and associate with yet another HAT protein, p/CAF (9). In contrast, SMRT and N-CoR, nuclear receptor corepressors, form complexes with Sin3 and histone deacetylase proteins (9). These results are consistent with the notion that the acetylation of histones destabilizes nucleosomes and relieves transcriptional repression by allowing transcription factors to access recognition elements, whereas deacetylation of the histones stabilizes the repressed state. More recently, the histone arginine methyltransferases CARM1 and PRMT1 were newly defined as transcriptional coactivators of nuclear receptors (4, 40). NSD1 and
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