TRIM25 targets p300 for degradation.

p300 is an important transcriptional co-factor. By stimulating the transfer of acetyl residues onto histones and several key transcription factors, p300 enhances transcriptional initiation and impacts cellular processes including cell proliferation and cell division. Despite its importance for cellular homeostasis, its regulation is poorly understood.

Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy.

Unlabelled: The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy.

TRIMming Down Hormone-Driven Cancers: The Biological Impact of TRIM Proteins on Tumor Development, Progression and Prognostication.

The tripartite motif (TRIM) protein family is attracting increasing interest in oncology. As a protein family based on structure rather than function, a plethora of biological activities are described for TRIM proteins, which are implicated in multiple diseases including cancer. With hormone-driven cancers being among the leading causes of cancer-related death, TRIM proteins have been described to portrait tumor suppressive or oncogenic activities in these tumor types.

Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices.

Using human embryonic, adult and cancer stem cells/stem cell-like cells (SCs), we demonstrate that DNA replication speed differs in SCs and their differentiated counterparts. While SCs decelerate DNA replication, differentiated cells synthesize DNA faster and accumulate DNA damage. Notably, both replication phenotypes depend on p53 and polymerase iota (POLι).

Regulation of p53 by E3s.

More than 40 years of research on p53 have given us tremendous knowledge about this protein. Today we know that p53 plays a role in different biological processes such as proliferation, invasion, pluripotency, metabolism, cell cycle control, ROS (reactive oxygen species) production, apoptosis, inflammation and autophagy. In the nucleus, p53 functions as a bona-fide transcription factor which activates and represses transcription of a number of target genes.

Delay in development and behavioural abnormalities in the absence of p53 in zebrafish.

p53 is well-known for its tumour-suppressive activity. However, in the past decade it became clear that p53 is also involved in other processes including stem cell proliferation, differentiation and animal development. To investigate the role of p53 in early embryonic development, we targeted p53 by CRISPR/Cas9 to make a p53 knock-out zebrafish (Danio rerio).

Amniotic Fluid Cells, Stem Cells, and p53: Can We Stereotype p53 Functions?

In recent years, great interest has been devoted to finding alternative sources for human stem cells which can be easily isolated, ideally without raising ethical objections. These stem cells should furthermore have a high proliferation rate and the ability to differentiate into all three germ layers. Amniotic fluid, ordinarily discarded as medical waste, is potentially such a novel source of stem cells, and these amniotic fluid derived stem cells are currently gaining a lot of attention.

Fam83F induces p53 stabilisation and promotes its activity.

p53 is one of the most important tumour suppressor proteins currently known. It is activated in response to DNA damage and this activation leads to proliferation arrest and cell death. The abundance and activity of p53 are tightly controlled and reductions in p53's activity can contribute to the development of cancer.

The transient production of anti-TNF-α antibody Adalimumab and a comparison of its characterization to the biosimilar Cinorra.

Recombinant antibodies have emerged over the last few decades as the fastest growing class of therapeutic proteins for autoimmune diseases. Post-translation modifications of antibodies produced by human cell lines are highly consistent with those existing in natural human proteins and this is a major advantage of utilizing these cell lines. Cinorra is a biosimilar form of the antibody Adalimumab, which is an antagonist of TNF-α used for the treatment of autoimmune diseases.

p53 Is Active in Human Amniotic Fluid Stem Cells.

Despite increasing interest in human amniotic fluid cells, very little is known about the regulation and function of p53 in this cell type. In this study, we show that undifferentiated human amniotic fluid cells express p53, yet at lower levels than in cancer cells. The p53 protein in amniotic fluid cells is mainly localized in the nuclei, however, its antiproliferative activity is compromised in these cells.

Antisense oligonucleotide-mediated MDM4 exon 6 skipping impairs tumor growth.

MDM4 is a promising target for cancer therapy, as it is undetectable in most normal adult tissues but often upregulated in cancer cells to dampen p53 tumor-suppressor function. The mechanisms that underlie MDM4 upregulation in cancer cells are largely unknown. Here, we have shown that this key oncogenic event mainly depends on a specific alternative splicing switch.

Expression screening using a Medaka cDNA library identifies evolutionarily conserved regulators of the p53/Mdm2 pathway.

Background: The p53 tumor suppressor protein is mainly regulated by alterations in the half-life of the protein, resulting in significant differences in p53 protein levels in cells. The major regulator of this process is Mdm2, which ubiquitinates p53 and targets it for proteasomal degradation. This process can be enhanced or reduced by proteins that associate with p53 or Mdm2 and several proteins have been identified with such an activity.

Hierarchical Micro-Nano Surface Topography Promotes Long-Term Maintenance of Undifferentiated Mouse Embryonic Stem Cells.

Understanding of stem cell-surface interactions and, in particular, long-term maintenance of stem cell pluripotency on well-defined synthetic surfaces is crucial for fundamental research and biomedical applications of stem cells. Here, we show that synthetic surfaces possessing hierarchical micro-nano roughness (MN-surfaces) promote long-term self-renewal (>3 weeks) of mouse embryonic stem cells (mESCs) as monitored by the expression levels of the pluripotency markers octamer-binding transcription factor 4 (Oct4), Nanog, and alkaline phosphatase. On the contrary, culturing of mESCs on either smooth (S-) or nanorough polymer surfaces (N-surfaces) leads to their fast differentiation.

New tricks for p53 regulation - restraint by protein coding RNAs.

P53 is most well-known for its tumor suppressive function in differentiated cells. Its activities in embryonic stem cells (ESCs) are, however, less well understood. For many years it was thought that p53 is not active at all in ESCs and unable to elicit a DNA damage response in this cell type.

Tetramerization-defects of p53 result in aberrant ubiquitylation and transcriptional activity.

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.

Interaction of HPV E6 oncoproteins with specific proteasomal subunits.

The Human Papillomavirus E6 oncoproteins have the capacity to target several of their cellular interacting partners for proteasome mediated degradation, and recent proteomic analyses suggest a close involvement of E6 with the cellular proteasome machinery. In this study we have performed an extensive analysis of the capacity of different E6 oncoproteins to interact with specific proteasome components. We demonstrate that multiple subunits of the proteasome can be bound by different HPV E6 oncoproteins.

Meeting report: Signal transduction meets systems biology.

In the 21st century, systems-wide analyses of biological processes are getting more and more realistic. Especially for the in depth analysis of signal transduction pathways and networks, various approaches of systems biology are now successfully used. The EU FP7 large integrated project SYBILLA (Systems Biology of T-cell Activation in Health and Disease) coordinates such an endeavor.

PCNA-dependent accumulation of CDKN1A into nuclear foci after ionizing irradiation.

The cyclin-dependent kinase inhibitor CDKN1A/p21 confers cell-cycle arrest in response to DNA damage and inhibits DNA replication through its direct interaction with the proliferating cell nuclear antigen (PCNA) and cyclin/cyclin-dependent kinase complexes. Previously, we reported that in response to densely ionizing radiation CDKN1A rapidly is recruited to the sites of particle traversal, and that CDKN1A foci formation in response to heavy ions is independent of its transactivation by TP53. Here, we show that exposure of normal human fibroblasts to X-rays or to H2O2 also induces nuclear accumulations of CDKN1A.

p53 in stem cells.

p53 is well known as a "guardian of the genome" for differentiated cells, in which it induces cell cycle arrest and cell death after DNA damage and thus contributes to the maintenance of genomic stability. In addition to this tumor suppressor function for differentiated cells, p53 also plays an important role in stem cells. In this cell type, p53 not only ensures genomic integrity after genotoxic insults but also controls their proliferation and differentiation.

LiCl induces TNF-α and FasL production, thereby stimulating apoptosis in cancer cells.

Background: The incidence of cancer in patients with neurological diseases, who have been treated with LiCl, is below average. LiCl is a well-established inhibitor of Glycogen synthase kinase-3, a kinase that controls several cellular processes, among which is the degradation of the tumour suppressor protein p53. We therefore wondered whether LiCl induces p53-dependent cell death in cancer cell lines and experimental tumours.

Regulation of p53 in embryonic stem cells.

Despite an increasing interest in the role of the p53 tumour suppressor protein in embryonic stem cells, not much is known about its regulation in this cell type. We show that the relatively high amount of p53 protein correlates with a higher amount of p53 RNA in ES cells compared to differentiated cells. Moreover, p53 RNA is more stable in embryonic stem cells and the p53 protein is more often transcribed.

Mdm2 facilitates the association of p53 with the proteasome.

The ubiquitin ligase Mdm2 targets the p53 tumor suppressor protein for proteasomal degradation. Mutating phosphorylation sites in the central domain of Mdm2 prevents p53 degradation, although it is still ubiquitylated, indicating that Mdm2 has a post-ubiquitylation function for p53 degradation. We show that Mdm2 associates with several subunits of the 19S proteasome regulatory particle in a ubiquitylation-independent manner.

Regulation of p53--insights into a complex process.

The p53 protein is one of the most important tumor suppressor proteins. Normally, the p53 protein is in a latent state. However, when its activity is required, e.

Nuclear accumulation and activation of p53 in embryonic stem cells after DNA damage.

Background: P53 is a key tumor suppressor protein. In response to DNA damage, p53 accumulates to high levels in differentiated cells and activates target genes that initiate cell cycle arrest and apoptosis. Since stem cells provide the proliferative cell pool within organisms, an efficient DNA damage response is crucial.