Selective metabolic regulations by p53 mutant variants in pancreatic cancer.

Background: Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear.

An LRP1-binding motif in cellular prion protein replicates cell-signaling activities of the full-length protein.

Low-density lipoprotein receptor-related protein-1 (LRP1) functions as a receptor for nonpathogenic cellular prion protein (PrPC), which is released from cells by ADAM (a disintegrin and metalloproteinase domain) proteases or in extracellular vesicles. This interaction activates cell signaling and attenuates inflammatory responses. We screened 14-mer PrPC-derived peptides and identified a putative LRP1 recognition motif in the PrPC sequence spanning residues 98-111.

An antibody that targets cell-surface glucose-regulated protein-78 inhibits expression of inflammatory cytokines and plasminogen activator inhibitors by macrophages.

Glucose-regulated protein-78 (Grp78) is an endoplasmic reticulum chaperone, which is secreted by cells and associates with cell surfaces, where it functions as a receptor for activated α -macroglobulin (α M) and tissue-type plasminogen activator (tPA). In macrophages, α M and tPA also bind to the transmembrane receptor, LDL receptor-related protein-1 (LRP1), activating a cell-signaling receptor assembly that includes the NMDA receptor (NMDA-R) to suppress innate immunity. Herein, we demonstrate that an antibody targeting Grp78 (N88) inhibits NFκB activation and expression of proinflammatory cytokines in bone marrow-derived macrophages (BMDMs) treated with the toll-like receptor-4 (TLR4) ligand, lipopolysaccharide, or with agonists that activate TLR2, TLR7, or TLR9.

p53-driven lipidome influences non-cell-autonomous lysophospholipids in pancreatic cancer.

Adaptation of the lipid metabolism participates  in cancer pathogenesis, facilitating energy storage and influencing cell fate and control of molecular signalling. The tumour suppressor protein p53 is a molecular hub of cell metabolism, supporting antioxidant capabilities and counteracting oncogene-induced metabolic switch. Despite extensive work has described the p53-dependent metabolic pathways, a global profiling of p53 lipidome is still missing.

p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer.

Somatic inactivation of p53 (TP53) mainly occurs as missense mutations that lead to the acquisition of neomorphic mutant protein forms. p53 mutants have been postulated to exert gain-of-function (GOF) effects, including promotion of metastasis and drug tolerance, which generally contribute to the acquisition of the lethal phenotype. Here, by integrating a p53 -dependent transcriptomic analysis with chromatin accessibility (ATAC-seq) profiling, we shed light on the molecular basis of a p53 mutant-dependent drug-tolerant phenotype in pancreatic cancer.

Understanding p53 tumour suppressor network.

The mutation of TP53 gene affects half of all human cancers, resulting in impairment of the regulation of several cellular functions, including cell cycle progression and cell death in response to genotoxic stress. In the recent years additional p53-mediated tumour suppression mechanisms have been described, questioning the contribution of its canonical pathway for tumour suppression. These include regulation of alternative cell death modalities (i.

NUAK2 and RCan2 participate in the p53 mutant pro-tumorigenic network.

Most inactivating mutations in TP53 gene generates neomorphic forms of p53 proteins that experimental evidence and clinical observations suggest to exert gain-of-function effects. While massive effort has been deployed in the dissection of wild type p53 transcriptional programme, p53 mutant pro-tumorigenic gene network is still largely elusive. To help dissecting the molecular basis of p53 mutant GOF, we performed an analysis of a fully annotated genomic and transcriptomic human pancreatic adenocarcinoma to select candidate players of p53 mutant network on the basis their differential expression between p53 mutant and p53 wild-type cohorts and their prognostic value.

Fibrinolysis protease receptors promote activation of astrocytes to express pro-inflammatory cytokines.

Background: Astrocytes contribute to the crosstalk that generates chronic neuro-inflammation in neurological diseases; however, compared with microglia, astrocytes respond to a more limited continuum of innate immune system stimulants. Recent studies suggest that the fibrinolysis system may regulate inflammation. The goal of this study was to test whether fibrinolysis system components activate astrocytes and if so, elucidate the responsible biochemical pathway.

Plasminogen Receptors in Human Malignancies: Effects on Prognosis and Feasibility as Targets for Drug Development.

The major proteases that constitute the fibrinolysis system are tightly regulated. Protease inhibitors target plasmin, the protease responsible for fibrin degradation, and the proteases that convert plasminogen into plasmin, including tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). A second mechanism by which fibrinolysis is regulated involves exosite interactions, which localize plasminogen and its activators to fibrin, extracellular matrix (ECM) proteins, and cell surfaces.