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

A TLR2 ligand suppresses inflammation by modulation of chemokine receptors and redirection of leukocyte migration

Toll-like receptors orchestrate rapid local protective innate-immune responses to invading pathogens and optimize leukocyte priming of subsequent adaptive responses. Paradoxically, systemic excess of the TLR2 ligand, bacterial lipoprotein (BLP), suppresses peripheral inflammatory responses. Here, we demonstrate that this phenomenon is regulated via the TLR2-dependent, cell-autonomous down-regulation of inflammatory chemokine receptor expression on a variety of leukocyte subsets. Remarkably, BLP mediated no effect on constitutive chemokine receptor expression. By tracking adoptively transferred wild-type and TLR2(-/-) leukocytes in vivo, we observed that BLP mediated chemokine receptor switching directed leukocytes away from inflamed sites toward secondary lymphoid organs. These data highlight a novel role for TLR ligands, such as BLP, in regulating leukocyte retention and migration away from innate immune lesions via discrete constitutive and inflammatory chemokine receptor regulatio