Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The LKB1 serine/threonine kinase is a tumour suppressor responsible for the inherited familial cancer disorder Peutz-Jeghers syndrome and is inactivated in a large percentage of human lung cancers. LKB1 acts a master kinase, directly phosphorylating and activating a family of 14 AMPK (AMP-activated protein kinase)-related kinases which control cell metabolism, cell growth and cell polarity. In this issue of the Biochemical Journal, Hardie and colleagues discover an alternative splice form of LKB1 that alters the C-terminus of the protein containing a few known sites of post-translational regulation. Although widely expressed, the short isoform (LKB1(s)) is the sole splice isoform expressed in testes, and its expression peaks at the time of spermatid maturation. Male mice lacking the LKB1(s) isoform have dramatic defects in spermatozoa, resulting in sterility.
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PMID:LKB1: cancer, polarity, metabolism, and now fertility. 1877 45

Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/ STK11 serine/threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies. Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice. Consistent with a central role for mTORC1 in these tumors, rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1+/- mice. However, the key targets of mTORC1 in LKB1-deficient tumors remain unknown. We demonstrate here that these polyps, and LKB1- and AMPK-deficient mouse embryonic fibroblasts, show dramatic up-regulation of the HIF-1alpha transcription factor and its downstream transcriptional targets in an rapamycin-suppressible manner. The HIF-1alpha targets hexokinase II and Glut1 are up-regulated in these polyps, and using FDG-PET, we demonstrate that LKB1+/- mice show increased glucose utilization in focal regions of their GI tract corresponding to these gastrointestinal hamartomas. Importantly, we demonstrate that polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels. Furthermore, like HIF-1alpha and its target genes, the FDG-PET signal in the GI tract of these mice is abolished by rapamycin treatment. These findings suggest a number of therapeutic modalities for the treatment and detection of hamartomas in PJS patients, and potential for the screening and treatment of the 30% of sporadic human lung cancers bearing LKB1 mutations.
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PMID:mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. 1954 9

The familial cancer syndrome Birt-Hogg-Dube syndrome is characterised by the development of skin (fibrofolliculomas) and renal tumours (and lung cysts) and is caused by mutations in the FLCN tumour suppressor gene. Though the FLCN gene product (folliculin) has been linked to the regulation of a variety of signalling pathways (e.g. the mTOR, AMPK, TGFbeta and hyoxia-responsive genes) the precise function of the folliculin protein is not well-defined. In order to identify potential novel pathways linked to folliculin function we analysed paired isogenic folliculin-deficient and folliculin-expressing cell lines by gene expression and protein (Kinexus) arrays. Gene expression microarray analysis in the folliculin +/- non-renal cancer line (FTC133), revealed 708 differentially expressed targets (fold change >2 and p<0.001) with enrichment of genes in the cadherin and Wnt signalling pathways. Comparison of the differentially expressed genes in the FTC133 datasets and previously reported gene expression data for a folliculin-deficient renal tumour and the UOK257 renal cell carcinoma cell line, revealed that RAB27B was dysregulated in all three datasets (increased expression in folliculin-deficient cells). The Kinexus protein array analysis suggested 73 candidate, differentially expressed, proteins and further investigation by western blot analysis of 5 candidates that were also differentially expressed in the FTC133 gene expression microarray data, revealed that EIF2AK2 (PKR) and CASP1 were reduced and PLCG2 was increased in folliculin-deficient FTC133 cells and in a BHD renal tumour. In view of the role of CASP1 in apoptosis we investigated whether other apoptosis-related proteins might be regulated by folliculin and found increased levels of SMAC/Diablo and HtrA2 in folliculin-expressing FTC133 cells. These findings identify novel pathways and targets linked to folliculin tumour suppressor activity.
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PMID:Gene expression and protein array studies of folliculin-regulated pathways. 2315 28