Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate whether genetic alteration of the STK11 (serine/threonine kinase 11)/LKB1 tumor-suppressor gene is involved in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the entire encoding exons and flanking intronic sequences of the STK11/LKB1 gene were analysed with direct genomic sequencing of 15 HNSCC specimens. A novel missense mutation with presumed loss of heterozygosity (LOH) and 10 polymorphisms were identified in these samples. The novel mutation of STK11/LKB1 at nucleotide position 613 G --> A, which causes the amino-acid substitution from alanine to threonine at residue 205 within the catalytic kinase domain, was identified in cell line RPMI 2650. To further determine whether this point mutation affects the gene function, constructs of the wild type and A205T mutant of the STK11/LKB1 gene expression vectors were created and transfected into RPMI 2650 cells. Our results showed that the reintroduction of the wild-type but not the mutant STK11/LKB1 construct into RPMI 2650 cells induced suppression of the cell growth. The mutation also affected the kinase activity of the Stk11/Lkb1 protein. This led us to conclude that the A205T point mutation of the STK11/LKB1 gene produces functionally inactive proteins. This is the first described mutation of the STK11/LKB1 gene in HNSCC. While the mutation frequency of the STK11/LKB1 gene in HNSCC remains to be determined in future studies, our data strongly suggests that STK11/LKB1 is involved in the carcinogenesis of HNSCC.
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PMID:A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma. 1640 37

The LKB1/STK11 serine/threonine kinase is mutated in Peutz-Jeghers syndrome and various sporadic cancers such as lung adenocarcinoma. We show here that LKB1 forms a complex with LMO4, GATA-6, and Ldb1, and enhances GATA-mediated transactivation in a kinase-dependent manner. We further demonstrate that LKB1 has the potential to induce p21 expression in collaboration with LMO4, GATA-6, and Ldb1 through the p53-independent mechanism. Our findings suggest that LKB1 regulates GATA-mediated gene expression and that this activity of LKB1 may be important for its tumor suppressor function.
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PMID:The tumor suppressor LKB1 induces p21 expression in collaboration with LMO4, GATA-6, and Ldb1. 1658 Jun 34

The molecular genetic profiles that characterize pancreatic ductal neoplasia have taken shape recently with the help of immunohistochemistry and the establishment of the nomenclature describing pancreatic ductal tumorigenesis. K-ras mutations frequently occur early, changes in the expression and genetic integrity of the p16 gene appear in intermediate lesions, and the inactivation of the p53, DPC4, and BRCA2 genes occur late in the neoplastic progression. Tumor-suppressor genes inactivated in pancreatic cancer such as ALK5, TGFBR2, MKK4, and STK11/LKB1 have been identified, although their roles in tumor progression are not yet well defined. Additional discoveries in this tumor system may be on the horizon, will further refine the molecular genetic profiles for the disease, and should suggest some clinical uses for this fund of knowledge.
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PMID:Molecular genetics of ductal pancreatic neoplasia. 1703 Nov 13

LKB1 (also known as STK11) is a recently identified tumor suppressor gene whose mutation can lead to Peutz-Jeghers syndrome, which is characterized by gastrointestinal polyps and cancers of different organ systems. Approximately 30% of sporadic breast cancer samples express low levels of LKB1. This suggests that the LKB1 gene may be related to the tumorigenesis of breast cancer. We reintroduced LKB1 into MDA-MB-435 breast cancer cells that lack the LKB1 gene to investigate how overexpression of LKB1 affects tumor invasiveness and metastasis. Overexpression of the LKB1 protein in breast cancer cells resulted in significant inhibition of in vitro invasion. In vivo, LKB1 expression reduced tumor growth in the mammary fat pad, microvessel density, and lung metastasis. LKB1 overexpression was associated with down-regulation of matrix metalloproteinase-2, matrix metalloproteinase-9, vascular endothelial growth factor, and basic fibroblast growth factor mRNA and protein levels. Overexpression of the LKB1 protein in human breast cancer is significantly associated with a decrease in microvessel density. Our results indicate that LKB1 plays a negative regulatory role in human breast cancer, a finding that may lead to a new therapeutic strategy.
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PMID:Enhanced expression of LKB1 in breast cancer cells attenuates angiogenesis, invasion, and metastatic potential. 1711 42

Germline mutations of the serine/threonine kinase LKB1 (also known as STK11) lead to Peutz-Jeghers syndrome (PJS) that is associated with increased incidence of malignant cancers. However, the tumor suppressor function of LKB1 has not been fully elucidated. We applied yeast two-hybrid screening and identified that a novel WD-repeat protein WDR6 was able to interact with LKB1. Immunofluorescence staining revealed that WDR6 was localized in cytoplasm, similar to the localization of LKB1. Expression of LKB1 was able to inhibit colony formation of Hela cells. Interestingly, coexpression of WDR6 with LKB1 enhanced the inhibitory effect of LKB1 on Hela cell proliferation. Consistently, WDR6 was able to synergize with LKB1 in cell cycle G1 arrest in Hela cells. Coexpression of WDR6 and LKB1 was able to induce a cyclin-dependent kinase (CDK) inhibitor p27(Kip1). Furthermore, the stimulatory effect of LKB1 on p27(Kip1) promoter activity was significantly elevated by coexpression with WDR6. Collectively, these results provided initial evidence that WDR6 is implicated in the cell growth inhibitory pathway of LKB1 via regulation of p27(Kip1).
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PMID:Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction. 1721 28

Peutz-Jeghers syndrome (PJS) is characterized by number of hamartomatous polyps in the gastrointestinal tract and by mucocutaneous hypermelanocytic lesions at different sites. Older patients have an increased risk of the cancers of small intestine, stomach, pancreas, colon, esophagus, ovary, testis, uterus, breast and lung. In majority of PJS cases, the germline mutations in serine/threonine kinase STK11/LKB1 gene were found to be associated with disease. Here we report the results of a first mutational screen of STK11/LKB1 in PJS patients characterized in Slovak population. The first patient with unusual carcinoma of duodenum was a sporadic case and carried c.842delC change residing in a mutational C6 repeat hotspot. Neither the polyp nor the tumor of the patient displayed the loss of heterozygosity at the site of mutation suggesting different mechanism involved in the formation of polyp and tumor in this case. The second patient belonged to a three-generation family with typical PJS features but not cancers. Interestingly, the patient displayed concomitant occurrence of adenomatous and hamartomatous polyps. Molecular analysis revealed an IVS2+1A>G mutation that alters the second intron 5' splice site and was shown to lead to aberrant splicing mediated by the U12-dependent spliceosome. The same mutation was present in the 9 affected members of the family but in none of their normal relatives. We also observed novel c. IVS2+61G>A unclassified variant, and recurrent IVS2+24G>T and 3UTR+129C>T polymorphisms. Based on the achieved results, we could offer predictive genetic testing and counseling to other members of the patient's families.
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PMID:STK11/LKB1 germline mutations in the first Peutz-Jeghers syndrome patients identified in Slovakia. 1731 81

Colorectal cancer (CRC) is among the most prevalent and preventable forms of cancer worldwide, accounting for over 600,000 deaths in 2005. Both genetic and environmental factors contribute to cancer etiology and estimates suggest that at least one third of CRC has a familial component. There is increased awareness of a strong genetic component to CRC risk, with the identification of several high penetrance alleles that predict increased CRC susceptibility. These include familial adenomatous polyposis (FAP), linked to mutations or deletions of the APC tumor suppressor gene, as well as Lynch syndrome (formerly known as hereditary non-polyposis colorectal cancer or HNPCC), which is linked to mutations or deletions of one or more mismatch repair genes including MLH1, MSH2 and MSH6. In addition, mutations in genes encoding key signaling molecules have been linked to autosomal dominant hamartomatous syndromes that are associated with increased susceptibility to CRC. These include Peutz-Jeghers syndrome, which is linked to mutations in STK11/LKB and Juvenile polyposis, which is linked to mutations in the genes encoding SMAD4 and BMPR1A. In addition to these high penetrance autosomal dominant alleles, recessive mutations in the MYH mismatch repair gene are associated with a phenotype similar to FAP. With the widespread availability of genetic testing for these alleles, physicians will be faced with a complex array of choices in terms of advocating who should be tested, when should such testing take place, how it should be conducted and interpreted and why it changes the management and outcomes for the patient and his or her family.
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PMID:Genetic testing in colorectal cancer: who, when, how and why. 1739 93

Germline mutations of the tumor suppressor gene LKB1/STK11 are responsible for the Peutz-Jeghers syndrome (PJS), an autosomal-dominant disorder characterized by mucocutaneous pigmentation, hamartomatous polyps, and an increased risk of associated malignancies. In this study, we assessed the presence of pathogenic mutations in the LKB1/STK11 gene in 46 unrelated PJS families, and also carried genotype-phenotype correlation in regard of the development of cancer in 170 PJS patients belonging to these families. All LKB1/STK11 variants detected with single-strand conformational polymorphism were confirmed by direct sequencing, and those without LKB1/STK11 mutation were further submitted to Southern blot analysis for detection of deletions/rearrangements. Statistical analysis for genotype-phenotype correlation was performed. In 59% (27/46) of unrelated PJS cases, pathogenic mutations in the LKB1/STK11 gene, including 9 novel mutations, were identified. The new mutations were 2 splice site deletion-insertions, 2 missenses, 1 nonsense, and 4 abnormal splice sites. Genotype-phenotype analysis did not yield any significant differences between patients carrying mutations in LKB1/STK11 versus those without mutations, even with respect to primary biliary adenocarcinoma. This study presents the molecular characterization and cancer occurrence of a large cohort of PJS patients, increases the mutational spectrum of LKB1/STK11 allelic variants worldwide, and provides a new insight useful for clinical diagnosis and genetic counseling of PJS families.
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PMID:Molecular and clinical characteristics in 46 families affected with Peutz-Jeghers syndrome. 1740 84

STK11 (serine/threonine kinase 11 ), a multi-functional protein reported recently, possibly participates in a broad range of cellular processes, including regulation of cell cycle, p53-mediated apoptosis, ras-induced cell transformation and cell polarization. An efficient expression of functional STK11 in Escherichia coli will promote the study on its structure and function. Inducible prokaryotic expression vector pET-Nus-STK11 (with Nus fusion tag) was constructed with pET-44a( + ) and the cDNA of STK11 gene cloned in our lab. pET-Nus-STK11 was then expressed in both BL21 (DE3) and Rosetta-gami (DE3)pLysS on the induction of IPTG. SDS-PAGE and Western blot indicated that recombinant Nus-STK11 obtained in BL21(DE3) was in the form of inclusion body, whereas that from Rosetta-gami (DE3)pLysS was mainly in soluble fraction, and accounted for 8.9% and 16.7% of the total protein, respectively. After purification and refolding, the obtained recombinant protein was carried into SMMC-7721 cells by Chariot to observe its influence on cell growth and cell cycle. Nus-STK 1 from BL21(DE3) was proved to be lack of any tumor-suppression activity, while a growth inhibitory ratio of 47.05% on SMMC-7721 cell was observed, and cell cycle progression of SMMC-7721 cells was also arrested from G0/G1 to S phase, with the Nus-STK11 from Rosetta-gami (DE3) pLysS, indicating that the above recombinant fusion protein from Rosetta-gami (DE3)pLysS had significant biological activity. This is the first report on functional recombinant STK11 protein expressed in Escherichia coli.
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PMID:[Expression of functional human STK11 protein in Escherichia coli]. 1743 29

We have isolated lethal mutations in the Drosophila lkb1 gene (dlkb1), the homolog of C. elegans par-4 and human LKB1 (STK11), which is mutated in Peutz-Jeghers syndrome. We show that these mutations disrupt spindle formation, resulting in frequent polyploid cells in larval brains. In addition, dlkb1 mutations affect asymmetric division of larval neuroblasts (NBs); they suppress unequal cytokinesis, abrogate proper localization of Bazooka, Par-6, DaPKC and Miranda, but affect neither Pins/Galphai localization nor spindle rotation. Most aspects of the dlkb1 phenotype are exacerbated in dlkb1 pins double mutants, which exhibit more severe defects than those observed in either single mutant. This suggests that Dlkb1 and Pins act in partially redundant pathways to control the asymmetry of NB divisions. Our results also indicate that Dlkb1 and Pins function in parallel pathways controlling the stability of spindle microtubules. The finding that Dlkb1 mediates both the geometry of stem cell division and chromosome segregation provides novel insight into the mechanisms underlying tumor formation in Peutz-Jeghers patients.
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PMID:The Drosophila Lkb1 kinase is required for spindle formation and asymmetric neuroblast division. 1750 18


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