Transcriptional activation of target genes represents an important component of the tumour-suppressor function of p53 and provides a functional link between p53 and various growth-regulatory processes, including cell cycle progression (p21/WAF1), DNA repair (GADD45) and apoptosis (bax). Here we use a differential cloning approach to identify the gene encoding insulin-like growth factor binding protein 3 (IGF-BP3) as a novel p53-regulated target gene. Induction of IGF-BP3 gene expression by wild-type but not mutant p53 is associated with enhanced secretion of an active form of IGF-BP3 capable of inhibiting mitogenic signalling by the insulin-like growth factor IGF-1. Our results indicate that IGF-BP3 may link p53 to potential novel autocrine/paracrine signalling pathways and to processes regulated by or dependent on IGF(s), such as cellular growth, transformation and survival.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

The NF-B/Rel family of transcription factors plays a key role in regulating inflammatory and immune responses and other programs of cell growth and survival. The five known mammalian Rel genes encode seven Rel-related proteins: RelA/p65; p105 and its processing product, p50; p100 and its processing product, p52; c-Rel; and RelB. Each contains an N-terminal Rel homology domain (ϳ300 amino acids) that mediates DNA binding, dimerization, and interaction with the IB family of NF-B/Rel inhibitors. RelA, c-RelA, and RelB contain C-terminal transactivation domains, but p50 and p52 do not. Each NF-B/Rel protein forms different homo-or heterodimers with other members of the family, which may contribute to the activation of specific target genes (1, 5).The prototypical NF-B complex is a p50/RelA heterodimer. NF-B is largely sequestered in the cytoplasm through its association with an IB inhibitor. Nuclear NF-B expression is induced by various stimuli, including proinflammatory cytokines, growth factors, DNA-damaging agents, and viral proteins (13). The activation of NF-B can be divided into two phases. The first phase involves cytoplasmic events culminating in the activation of the IB kinases (IKK1 and IKK2). These kinases promote N-terminal phosphorylation of serines 32 and 36 in IB␣, leading to its polyubiquitylation and proteasome-mediated degradation. The liberated NF-B complex rapidly translocates to the nucleus, ending the first phase (13). The second phase occurs primarily in the nucleus and involves posttranslational modification of the NF-B transcription factor complex or relevant histones surrounding NF-B target genes (5). These modifications determine both the strength and duration of the NF-B-mediated transcriptional response (5).One of the nuclear events is the reversible acetylation of RelA (4). Endogenous RelA is acetylated in a stimulus-coupled manner after activation of cells with tumor necrosis factor alpha (TNF-␣), phorbol myristate acetate, or other stimuli at multiple sites, including lysines 122, 123, 218, 221, and 310 (4, 17). The acetyltransferases p300 and CBP appear to play a major role in the in vivo acetylation of RelA (6,17). Sitespecific acetylation of RelA regulates discrete biological actions of the NF-B complex (5, 6). For example, acetylation of lysine 221 by p300/CBP increases the DNA binding affinity of RelA for the B enhancer and, together with acetylation of lysine 218, impairs assembly of RelA with newly synthesized IB␣, which shuttles in and out of the nucleus. Acetylation of lysine 310 does not modulate DNA binding or IB␣ assembly but markedly enhances the transcriptional activity of NF-B. Deacetylation of lysine 310 by histone deacetylase 3 (HDAC3) or SIRT1 inhibits the transcriptional activity of RelA and augments cellular apoptosis in response to 32). While it is clear that signal-coupled acetylation of RelA participates in the nuclear regulation of NF-B action (4, 17), many unanswered questions remain. Chief among these is how the acetylation of RelA is regulated.

Exposure of mammalian cells to hypoxia, radiation and certain chemotherapeutic agents promotes cell cycle arrest and/or apoptosis. Activation of p53 responsive genes is believed to play an important role in mediating such responses. In this study we identi®ed a novel gene, PA26, which maps to chromosome 6q21 and encodes at least three transcript isoforms, of which two are dierentially induced by genotoxic stress (UV, girradiation and cytotoxic drugs) in a p53-dependent manner. A functional p53-responsive element was identi®ed in the second intron of the PA26 gene, in consistence with a mechanism of transcriptional induction of the PA26 gene by p53. No clues to its functions were revealed by sequence analysis, although pronounced negative regulation by serum factors argues for a potential role of PA26 in growth regulation. Immunological analysis suggests that PA26 protein(s) is localized to the cell nucleus. Our results suggest that the PA26 gene is a novel p53 target gene with properties common to the GADD family of growth arrest and DNA damageinducible stress-response genes, and, thus, a potential novel regulator of cellular growth.