Medical Research Council

About: Medical Research Council is a government organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Malaria. The organization has 16430 authors who have published 19150 publications receiving 1475494 citations.

A Role for the ESCRT System in Cell Division in Archaea

Abstract: Archaea are prokaryotic organisms that lack endomembrane structures. However, a number of hyperthermophilic members of the Kingdom Crenarchaea, including members of the Sulfolobus genus, encode homologs of the eukaryotic endosomal sorting system components Vps4 and ESCRT-III (endosomal sorting complex required for transport–III). We found that Sulfolobus ESCRT-III and Vps4 homologs underwent regulation of their expression during the cell cycle. The proteins interacted and we established the structural basis of this interaction. Furthermore, these proteins specifically localized to the mid-cell during cell division. Overexpression of a catalytically inactive mutant Vps4 in Sulfolobus resulted in the accumulation of enlarged cells, indicative of failed cell division. Thus, the archaeal ESCRT system plays a key role in cell division.

SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland

Abstract: The pituitary gland adapts the proportion of each of its endocrine cell types to meet differing hormonal demands throughout life. There is circumstantial evidence that multipotent adult progenitor cells contribute to this plasticity, but these cells have not been identified. Here, we describe a small (<0.05%) population of progenitor cells in the adult pituitary gland. We show that these cells express SOX2, a marker of several early embryonic progenitor and stem cell types, and form “pituispheres” in culture, which can grow, form secondary spheres, and differentiate to all of the pituitary endocrine cell types, as well as folliculostellate cells. Differentiation of cells in the pituispheres was associated with the expression of nestin, SOX9, and S100. Cells expressing SOX2 and E-cadherin are found throughout Rathke's pouch (RP) in embryos but persist in the adult gland, mostly in a narrow zone lining the pituitary cleft, but also are scattered throughout the pituitary. However, unlike in embryonic RP, most of these SOX2+ cells in the adult gland also express SOX9 and S100. We suggest that this SOX2+/SOX9+ population represents transit-amplifying cells, whereas the SOX2+/SOX9− cells we identify are multipotent progenitor/stem cells persisting in the adult pituitary.

Targeted rescue of a destabilized mutant of p53 by an in silico screened drug

Abstract: The tumor suppressor p53 is mutationally inactivated in ≈50% of human cancers. Approximately one-third of the mutations lower the melting temperature of the protein, leading to its rapid denaturation. Small molecules that bind to those mutants and stabilize them could be effective anticancer drugs. The mutation Y220C, which occurs in ≈75,000 new cancer cases per annum, creates a surface cavity that destabilizes the protein by 4 kcal/mol, at a site that is not functional. We have designed a series of binding molecules from an in silico analysis of the crystal structure using virtual screening and rational drug design. One of them, a carbazole derivative (PhiKan083), binds to the cavity with a dissociation constant of ≈150 μM. It raises the melting temperature of the mutant and slows down its rate of denaturation. We have solved the crystal structure of the protein–PhiKan083 complex at 1.5-A resolution. The structure implicates key interactions between the protein and ligand and conformational changes that occur on binding, which will provide a basis for lead optimization. The Y220C mutant is an excellent “druggable” target for developing and testing novel anticancer drugs based on protein stabilization. We point out some general principles in relationships between binding constants, raising of melting temperatures, and increase of protein half-lives by stabilizing ligands. NMR screen oncogenic mutant protein stabilization virtual drug design crystal structure

The possible existence of multiple receptors for substance P.

Abstract: 1. The possible existence of multiple receptors for substance P (SP) was investigated by examining the relative pharmacological potencies of SP and related peptides in contracting guinea pig ileum, in potentiating electrically evoked contractions of rat vas deferens preparations and in competing for 3H-SP receptor binding in rat brain membranes, and by comparing the extent of cross-tachyphylaxis of various analogues with SP in the guinea pig ileum. 2. Different rank orders of potencies were observed among SP, its C-terminal fragments, analogues and related tachykinins in the different test systems, and these could not be explained by differential access to the target organ receptors. 3. In contrast to SP and physalaemin, both eledoisin and a metabolically stable SP analogue, [pGlu5, MePhe8, Sar9]-SP5-11 exhibited differential recovery from SP tachyphylaxis in the guinea pig ileum, and part of their spasmogenic action in this preparation was atropine-sensitive. 4. The results suggest the possible existence of multiple SP receptors, and the specificity of those in the brain may be different from those in the gut. The structural and pharmacological basis for subdividing tachykinins into SP-physalaemin and eledoisin-kassinin families is also discussed.