Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mycobacterium tuberculosis (M.tb.) replicates in host macrophages to cause tuberculosis. We have investigated the role of miRNAs in M.tb.-infected murine RAW264.7 cells and bone marrow-derived macrophages (BMDMs), focusing on miR-155, the most highly upregulated miRNA. We observed that miR-155 upregulation is directly linked to the attenuation of expression of BTB and CNC homology 1 (Bach1) and SH2-containing inositol 5'-phosphatase (SHIP1). Bach1 is a transcriptional repressor of haem oxygenase-1 (HO-1), whereas SHIP1 inhibits the activation of the serine/threonine kinase AKT. We hypothesize that M.tb.-induced miR-155 induction leads to repression of Bach1, which augments the expression of HO-1, a documented activator of the M.tb. dormancy regulon. SHIP1 repression facilitates AKT activation, which is required for M.tb. survival. In addition, M.tb.-induced miR-155 inhibits expression of cyclooxygenase-2 (Cox-2) and interleukin-6 (Il-6), two modulators of the innate immune response. Importantly, we observed that the virulence-associated secreted protein ESAT-6 plays a key role in miR-155 induction and its subsequent effects on Bach1 and SHIP1 repression. Inhibition of miR-155 hindered survival of M.tb. in RAW264.7 and in murine BMDMs. Thus, our results offer new insights into the role of miRNAs in modulation of the host innate immune response by M.tb. for its own benefit.
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PMID:Identification of a novel role of ESAT-6-dependent miR-155 induction during infection of macrophages with Mycobacterium tuberculosis. 2271 28

Genetic variation (rs372883C/T) in the 3'-untranslated region of BTB and CNC homology 1 (BACH1) has been associated with pancreatic ductal adenocarcinoma (PDAC) risk in our previous genome-wide association study; however, the action roles of this genetic variation in PDAC remains unknown. Methods:BACH1 expression was measured by quantitative real-time PCR, Western blot and immunohistochemistry. The effects of BACH1 on cell proliferation and sensitivity to gemcitabine were examined by alteration of BACH1 expression in PDAC cells. Angiogenesis was determined in vitro using a human umbilical vein endothelial cell model. Reporter gene assays were conducted to compare the effects of microRNA-1257 on rs372883 variation. The associations between rs372883 variants and survival time in patients treated with gemcitabine were estimated by logistic regression. Results: We found substantially lower BACH1 expression in PDAC compared with normal pancreatic tissues and the rs372883T allele had significantly lower BACH1 levels than the rs372883C allele in both tumor and normal tissues. Knockdown of BACH1 expression provoked proliferation of PDAC cells and angiogenesis, which might result from upregulation of hemeoxygenase-1 that evokes oncogenic AKT and ERK signaling. The rs372883T>C change inhibits interaction of BACH1 with microRNA-1257, resulting in increased BACH1 expression. PDAC patients with the rs372883T allele were more resistant to gemcitabine and had shorter survival time compared with those with the rs372883C allele. Conclusion: These results shed light on the mechanism underlying the associations of BACH1 rs372883 variation with risk of developing PDAC and differential gemcitabine sensitivity in patients.
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PMID:Functional role of BTB and CNC Homology 1 gene in pancreatic cancer and its association with survival in patients treated with gemcitabine. 2993 Jul 35

Transcriptional factor BTB and CNC homology 1 (Bach1) has been linked to tumor progression and metastasis, but the mechanisms underlying the effects of Bach1 on tumor growth and metastasis are largely uncharacterized. Here, we report that Bach1 expression was significantly higher in human epithelial ovarian cancer (EOC) tissues than in normal ovarian tissues and that higher levels of Bach1 were associated with tumor stage and poorer overall and progression-free survival. We found that Bach1 enhanced the expression of epithelial-mesenchymal transition (EMT) genes, including Slug and Snail, and promoted cell migration by recruiting HMGA2 in the human EOC cell line A2780. Bach1 overexpression enhanced and Bach1 knockout reduced the expression of Slug and the metastasis of EOC cells in a tumor metastasis mouse model. Bach1 expression was positively correlated with Slug and HMGA2 expression in human ovarian cancer tissues. In addition, Bach1 activated p-AKT and p-p70S6K, increased the expression of cyclin D1, and promoted the growth of ovarian cancer cells in vitro and tumor xenografts in vivo. Together, our findings reveal that Bach1 enhances tumor growth and recruits HMGA2 to promote EMT and ovarian cancer metastasis.
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PMID:BTB and CNC homology 1 (Bach1) promotes human ovarian cancer cell metastasis by HMGA2-mediated epithelial-mesenchymal transition. 3065 10