Menin and p53 have non-synergistic effects on tumorigenesis in mice

<p>Abstract</p> <p>Background</p> <p>While it is now more than a decade since the first description of the gene mutation underlying the tumour predisposition syndrome multiple endocrine neoplasia type 1 (MEN1), the mechanism by which its protein product menin acts to prevent development of tumours is still poorly understood.</p> <p>Methods</p> <p>We undertook a genetic experiment to assess whether menin synergises with p53. Mice carrying various combinations of <it>Men1</it> and <it>Trp53</it> mutations were generated then survival and pathology assessed.</p> <p>Results</p> <p>While homozygous loss of <it>Trp53</it> in mice resulted in early onset, aggressive tumours and profoundly reduced lifespan, heterozygous loss of either <it>Trp53</it> or <it>Men1</it> caused later onset disease, with a spectrum of tumours characteristic of each tumour suppressor gene. Loss of one copy of <it>Men1</it> in animals also lacking both alleles of <it>Trp53</it> did not exacerbate phenotype, based on survival, animal weight or sites of pathology, compared to <it>Trp53</it> deletion alone. Dual heterozygous deletion of <it>Men1</it> and <it>Trp53</it> resulted in a small reduction in lifespan compared to the individual mutations, without new tumour sites. In the adrenal, we observed development of cortical tumours in dual heterozygous animals, as we have previously seen in <it>Men1</it>^+/− animals, and there was loss of heterozygosity at the <it>Men1</it> allele in these tumours. Median number of pathology observations per animal was increased in dual heterozygous animals compared with heterozygous loss of <it>Trp53</it> alone.</p> <p>Conclusions</p> <p>Simultaneous heterozygous deletion of <it>Men1</it> in animals with either heterozygous or homozygous deletion of <it>Trp53</it> did not result in formation of tumours at any new sites, implying additive rather than synergistic effects of these pathways. Mice that were <it>Men1</it>^+/− in addition to <it>Trp53</it>^+/− had tumours in endocrine as well as other sites, implying that increase in total tumour burden, at sites typically associated with either <it>Men1</it> or <it>Trp53</it> loss, contributed to the slight decrease in survival in <it>Men1</it>^+/−: <it>Trp53</it>^+/− animals in comparison with their littermates.</p

Structural Analysis of S100A8 Complex with Zinc and Calcium: A General Protocol for the Study of S100 Proteins in the Presence of Divalent Cations by X-Ray Crystallography

International audienc

Human calprotectin is an iron-sequestering host-defense protein

Human calprotectin (CP) is a metal-chelating antimicrobial protein of the innate immune response. The current working model states that CP sequesters manganese and zinc from pathogens. We report the discovery that CP chelates iron and deprives bacteria of this essential nutrient. Elemental analysis of CP-treated growth medium establishes that CP reduces the concentrations of manganese, iron and zinc. Microbial growth studies reveal that iron depletion by CP contributes to the growth inhibition of bacterial pathogens. Biochemical investigations demonstrate that CP coordinates Fe(II) at an unusual hexahistidine motif, and the Mössbauer spectrum of [superscript 57]Fe(II)-bound CP is consistent with coordination of high-spin Fe(II) at this site (δ = 1.20 mm/s, ΔE[subscript Q] = 1.78 mm/s). In the presence of Ca(II), CP turns on its iron-sequestering function and exhibits subpicomolar affinity for Fe(II). Our findings expand the biological coordination chemistry of iron and support a previously unappreciated role for CP in mammalian iron homeostasis.National Institutes of Health (U.S.) (NIH grant 1DP2OD007045)Alfred P. Sloan FoundationKinship Foundation (Searle Scholars Program award)National Institutes of Health (U.S.) (MIT Center for Environmental Health Sciences (NIH P30-ES002109))National Science Foundation (U.S.) (NSF Graduate Research Fellowship

Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection

Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options(1,2). Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection(3). Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration(4). We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors(5,6). Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsi