Pharmacological targeting of nonsense mutant TP53 and PTEN in cancer

The TP53 tumor suppressor gene encodes p53 and is inactivated by mutations in around half of all human tumors. Approximately 11% of TP53 mutations are nonsense mutations, resulting in the premature termination of translation and the production of truncated and non-functional p53 proteins. Aminoglycosides such as G418 are known to induce translational readthrough, a process in which the ribosome overcomes the stop signal introduced by a nonsense mutation and translates full-length protein. However, the clinical use of aminoglycosides is restricted due to severe side effects. We have demonstrated that combination treatments with proteasome inhibitors or compounds that disrupt the binding of p53 to the ubiquitin ligase MDM2 can synergistically enhance the levels of fulllength p53, improving the efficacy of readthrough compared to aminoglycosides alone. These combinations were proven to produce at least partially active fulllength p53, as shown by the suppression of cell growth and the induction of cell death. In parallel, chemical library screenings led to the discovery of two novel compounds, C47 and C61, showing readthrough activity and synergizing with G418 and eRF3 degraders CC-885 and CC-90009, respectively. Remarkably, C47 also exhibit readthrough activity for nonsense mutant phosphatase and tensin homolog (PTEN), expanding the scope for targeted cancer therapies. Furthermore, we have identified the 5-fluorouracil (5-FU) metabolite 5-Fluorouridine (FUr) as a potent readthrough-inducing compounds capable restoring full-length p53 expression in cells harboring nonsense mutant TP53. In vivo studies further substantiated the capability of FUr to reinstate full-length p53 expression in human tumor xenografts with TP53 R213X nonsense mutations. Finally, the first Trp53 R210X nonsense mutant knock-in mouse model has been generated. R210X corresponds to human TP53 R213X. Observations on tumor development, lifespan and other phenotypic traits in these mice provide valuable insights into the impact of TP53 nonsense mutation in a multi-organ system. These results also provide a platform for the preclinical evaluation of novel therapeutic strategies for targeting nonsense mutant TP53. In summary, these findings offer a multi-faceted approach towards understanding TP53 nonsense mutations and advancing targeted cancer therapy through pharmacological induction of translational readthrough. The discovery of novel readthrough inducing compounds, the application of combination therapy in translational readthrough, the discovery of a novel therapeutic application for 5- FU and its metabolite FUr, as well as the generation of a novel animal model collectively set the stage for the further development of personalized treatments for patients with tumors harboring nonsense mutant TP53

Chemical regulators of epithelial plasticity reveal a nuclear receptor pathway controlling myofibroblast differentiation

Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse transforming growth factor β (TGF-β)-induced epithelial-mesenchymal transition. In addition to TGF-β receptor kinase inhibitors, we identified small molecule epithelial plasticity modulators including a naturally occurring hydroxysterol agonist of the liver X receptors (LXRs), members of the nuclear receptor transcription factor family. Endogenous and synthetic LXR agonists tested in diverse cell models blocked α-smooth muscle actin expression, myofibroblast differentiation and function. Agonist-dependent LXR activity or LXR overexpression in the absence of ligand counteracted TGF-β-mediated myofibroblast terminal differentiation and collagen contraction. The protective effect of LXR agonists against TGF-β-induced pro-fibrotic activity raises the possibility that anti-lipidogenic therapy may be relevant in fibrotic disorders and advanced cancer

Pärandvara inventuuri läbiviimine kohtutäituri büroos

http://tartu.ester.ee/record=b2659941~S

Andekuse mõiste ja andekat õpilast toetavate tugimeetmete käsitlus Eesti õiguses ning Harjumaa koolides

https://www.ester.ee/record=b5238554*es

Simultaneous induction of stimulatory and inhibitory signals by PDGF

AbstractPlatelet-derived growth factor (PDGF) exerts its effects on cells via binding to structurally similar α- and β-tyrosine kinase receptors. Ligand binding induces receptor dimerization and autophosphorylation which allows docking of SH2 domain containing signal transduction molecules. At least 10 different SH2 domain molecules bind in a specific manner to 11 identified autophosphorylated tyrosine residues in the PDGF β-receptor, thereby initiating signaling pathways leading to cell growth and motility. Available information indicates that there is considerable cross-talk between different signaling pathways, and that stimulatory and inhibitory signals often are initiated in parallel

Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom

<p>Abstract</p> <p>Background</p> <p>The question of how genomic processes, such as gene duplication, give rise to co-ordinated organismal properties, such as emergence of new body plans, organs and lifestyles, is of importance in developmental and evolutionary biology. Herein, we focus on the diversification of the transforming growth factor-<it>β </it>(TGF-<it>β</it>) pathway – one of the fundamental and versatile metazoan signal transduction engines.</p> <p>Results</p> <p>After an investigation of 33 genomes, we show that the emergence of the TGF-<it>β </it>pathway coincided with appearance of the first known animal species. The primordial pathway repertoire consisted of four Smads and four receptors, similar to those observed in the extant genome of the early diverging tablet animal (<it>Trichoplax adhaerens</it>). We subsequently retrace duplications in ancestral genomes on the lineage leading to humans, as well as lineage-specific duplications, such as those which gave rise to novel Smads and receptors in teleost fishes. We conclude that the diversification of the TGF-<it>β </it>pathway can be parsimoniously explained according to the 2R model, with additional rounds of duplications in teleost fishes. Finally, we investigate duplications followed by accelerated evolution which gave rise to an atypical TGF-<it>β </it>pathway in free-living bacterial feeding nematodes of the genus Rhabditis.</p> <p>Conclusion</p> <p>Our results challenge the view of well-conserved developmental pathways. The TGF-<it>β </it>signal transduction engine has expanded through gene duplication, continually adopting new functions, as animals grew in anatomical complexity, colonized new environments, and developed an active immune system.</p

Transforming growth factor-β employs HMGA2 to elicit epithelial–mesenchymal transition

Epithelial–mesenchymal transition (EMT) occurs during embryogenesis, carcinoma invasiveness, and metastasis and can be elicited by transforming growth factor-β (TGF-β) signaling via intracellular Smad transducers. The molecular mechanisms that control the onset of EMT remain largely unexplored. Transcriptomic analysis revealed that the high mobility group A2 (HMGA2) gene is induced by the Smad pathway during EMT. Endogenous HMGA2 mediates EMT by TGF-β, whereas ectopic HMGA2 causes irreversible EMT characterized by severe E-cadherin suppression. HMGA2 provides transcriptional input for the expression control of four known regulators of EMT, the zinc-finger proteins Snail and Slug, the basic helix-loop-helix protein Twist, and inhibitor of differentiation 2. We delineate a pathway that links TGF-β signaling to the control of epithelial differentiation via HMGA2 and a cohort of major regulators of tumor invasiveness and metastasis. This network of signaling/transcription factors that work sequentially to establish EMT suggests that combinatorial detection of these proteins could serve as a new tool for EMT analysis in cancer patients