c-ABL チロシンキナーゼはp53依存性のp21誘導を介してDNA損傷応答における細胞運命決定を制御する

Tohoku University佐竹正延課

LncRNA HOTAIR regulates glucose transporter Glut1 expression and glucose uptake in macrophages during inflammation

Abstract Inflammation plays central roles in the immune response. Inflammatory response normally requires higher energy and therefore is associated with glucose metabolism. Our recent study demonstrates that lncRNA HOTAIR plays key roles in NF-kB activation, cytokine expression, and inflammation. Here, we investigated if HOTAIR plays any role in the regulation of glucose metabolism in immune cells during inflammation. Our results demonstrate that LPS-induced inflammation induces the expression of glucose transporter isoform 1 (Glut1) which controls the glucose uptake in macrophages. LPS-induced Glut1 expression is regulated via NF-kB activation. Importantly, siRNA-mediated knockdown of HOTAIR suppressed the LPS-induced expression of Glut1 suggesting key roles of HOTAIR in LPS-induced Glut1 expression in macrophage. HOTAIR induces NF-kB activation, which in turn increases Glut1 expression in response to LPS. We also found that HOTAIR regulates glucose uptake in macrophages during LPS-induced inflammation and its knockdown decreases LPS-induced increased glucose uptake. HOTAIR also regulates other upstream regulators of glucose metabolism such as PTEN and HIF1α, suggesting its multimodal functions in glucose metabolism. Overall, our study demonstrated that lncRNA HOTAIR plays key roles in LPS-induced Glut1 expression and glucose uptake by activating NF-kB and hence HOTAIR regulates metabolic programming in immune cells potentially to meet the energy needs during the immune response

Acquisition of classical CTX prophage from Vibrio cholerae O141 by El Tor strains aided by lytic phages and chitin-induced competence

The El Tor biotype of Vibrio cholerae O1, causing the current seventh pandemic of cholera, has replaced the classical biotype, which caused the sixth pandemic. The CTX prophages encoding cholera toxin in the two biotypes have distinct repressor (rstR) genes. Recently, new variants of El Tor strains that carry the classical type (CTXclass) prophage have emerged. These "hybrid" strains apparently originate through lateral gene transfer and recombination events. To explore possible donors of the CTXclass prophage and its mode of transfer, we tested environmental V. cholerae isolates for the presence of CTXclass prophage and mobility of the phage genome. Of the 272 environmental V. cholerae isolates tested, 6 were found to carry the CTXclass prophage; all of these belonged to the O141 serogroup. These O141 strains were unable to produce infectious CTXclass phage or to transmit the prophage to recipient strains in the mouse model of infection; however, the CTXclass prophage was acquired by El Tor strains when cultured with the O141 strains in microcosms composed of filtered environmental water, a chitin substrate, and a V. cholerae O141-specific bacteriophage. The CTXclass prophage either coexisted with or replaced the resident CTXET prophage, resulting in El Tor strains with CTX genotypes similar to those of the naturally occurring hybrid strains. Our results support a model involving phages and natural chitin substrate in the emergence of new variants of pathogenic V. cholerae. Furthermore, the O141 strains apparently represent an alternative reservoir of the CTXclass phage genome, because the classical V. cholerae O1 strains are possibly extinct

NOD2 Suppresses Colorectal Tumorigenesis via Downregulation of the TLR Pathways

Although NOD2 is the major inflammatory bowel disease susceptibility gene, its role in colorectal tumorigenesis is poorly defined. Here, we show that Nod2-deficient mice are highly susceptible to experimental colorectal tumorigenesis independent of gut microbial dysbiosis. Interestingly, the expression of inflammatory genes and the activation of inflammatory pathways, including NF-κB, ERK, and STAT3 are significantly higher in Nod2−/− mouse colons during colitis and colorectal tumorigenesis, but not at homeostasis. Consistent with higher inflammation, there is greater proliferation of epithelial cells in hyperplastic regions of Nod2−/− colons. In vitro studies demonstrate that, while NOD2 activates the NF-κB and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-κB and MAPK. Notably, NOD2-mediated downregulation of NF-κB and MAPK is associated with the induction of IRF4. Taken together, NOD2 plays a critical role in the suppression of inflammation and tumorigenesis in the colon via downregulation of the TLR signaling pathways