Crosstalk between c-Jun and TAp73alpha/beta contributes to the apoptosis-survival balance.

The p53-family member p73 plays a role in various cellular signaling pathways during development and growth control and it can have tumor suppressor properties. Several isoforms of p73 exist with considerable differences in their function. Whereas the functions of the N-terminal isoforms (TA and ΔNp73) and their opposing pro- and antiapoptotic roles have become evident, the functional differences of the distinct C-terminal splice forms of TAp73 have remained unclear.

Role of p53 serine 46 in p53 target gene regulation.

The tumor suppressor p53 plays a crucial role in cellular growth control inducing a plethora of different response pathways. The molecular mechanisms that discriminate between the distinct p53-responses have remained largely elusive. Here, we have analyzed the p53-regulated pathways induced by Actinomycin D and Etoposide treatment resulting in more growth arrested versus apoptotic cells respectively.

Behind the scenes: unravelling the molecular mechanisms of p53 target gene selectivity (Review).

The p53 protein is a tumor suppressor that plays a crucial role in cellular growth regulation inducing a plethora of response pathways. p53 post-translational modifications, p53-binding proteins, co-factors and the p53-family members p63 and p73 have all been described to contribute to p53 target gene regulation and hence cellular outcome. However, the molecular mechanisms that discriminate between the different p53-responses towards stress treatments have remained largely elusive.

Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 SHFM1 locus.

Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA-binding profiling by chromatin immunoprecipitation (ChIP), followed by deep sequencing (ChIP-seq) in primary human keratinocytes, and identified potential target genes and regulatory elements controlled by p63.

Mechanism of interferon-gamma mediated down-regulation of interleukin-10 gene expression.

Expression of the anti-inflammatory cytokine IL-10 is suppressed by the pro-inflammatory interferon gamma but the mechanism of this action is unknown. We analysed activity of IL-10 promoter luciferase reporter constructs in transfected RPMI 8226.1 B cells that were treated at -2 h with IFNgamma (1000 U/ml) followed by stimulation with LPS (100 ng/ml) at 0 h.

The novel p53 target gene IRF2BP2 participates in cell survival during the p53 stress response.

The tumor suppressor p53 contributes to the cellular fate after genotoxic insults, mainly through the regulation of target genes, thereby allowing e.g. repair mechanisms resulting in cell survival or inducing apoptosis.

Characterization of genome-wide p53-binding sites upon stress response.

The tumor suppressor p53 is a sequence-specific transcription factor, which regulates the expression of target genes involved in different stress responses. To understand p53's essential transcriptional functions, unbiased analysis of its DNA-binding repertoire is pivotal. In a genome-wide tiling ChIP-on-chip approach, we have identified and characterized 1546 binding sites of p53 upon Actinomycin D treatment.

Role of STAT3 in glucocorticoid-induced expression of the human IL-10 gene.

In the present report we have determined the molecular mechanisms, which govern the expression of the human IL-10 gene when induced by the glucocorticoid Methyl-Prednisolone (MP). Treatment of cells with MP at 10(-6) M will readily induce IL-10 in CD19+ primary B cells and in a human B cell line. Analysis of the IL-10 promoter showed a robust 18-fold induction and demonstrated that a potential GRE motif was not required, while mutation of the -120 STAT-motif strongly reduced MP-induced trans-activation.

The new frontier in cancer research: deciphering cancer epigenetics.

Cancer has long been known to be a disease caused by alterations in the genetic blueprint of cells. In the past decade it has become apparent that epigenetic alterations also underlie the etiology of cancer. Since epigenetic changes may be more facile to reverse than genetic lesions, much research has been invested in their characterization.

Targeted discovery tools: proteomics and chromatin immunoprecipitation-on-chip.

Despite the availability of several completely sequenced genomes, we are still, for the most part, ignorant about how genes interact and regulate each other within a given cell type to specify identity, function and cellular memory. A realistic model of cellular regulation based on current knowledge indicates that many interacting networks operate at the epigenetic, transcriptional, translational and post-translational levels, with feedback between the various levels. Protein-protein and protein-DNA interactions help to define which genes may be activated in a particular cell, and determine whether external cues cause activation or repression.

Regulation of HDM2 activity by the ribosomal protein L11.

The HDM2 protein plays an important role in regulating the stability and function of the p53 tumor suppressor protein. In this report, we show that the ribosomal protein L11 can interact with HDM2 and inhibit HDM2 function, thus leading to the stabilization and activation of p53. The inhibition of HDM2 activity by L11 shows some similarity to the previously described activity of ARF, and expression of either ARF or L11 can induce a p53 response.