Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germline mutations in the LKB1 (STK11) gene (chromosome sub-band 19p13.3) cause characteristic hamartomas and pigmentation to develop in patients with Peutz-Jeghers syndrome. Peutz-Jeghers syndrome carries an overall risk of cancer that may be up to 20 times that of the general population and Peutz-Jeghers patients are at increased risk of benign and malignant ovarian tumours, particularly granulosa cell tumours. Loss of heterozygosity (allele loss, LOH) has been reported in about 50% of ovarian cancers on 19p13.3. LKB1 is therefore a candidate tumour suppressor gene for sporadic ovarian tumours. We found allele loss at the marker D19S886 (19p13.3) in 12 of 49 (24%) sporadic ovarian adenocarcinomas. Using SSCP analysis, we screened ten ovarian cancers with LOH, 35 other ovarian cancers and 12 granulosa cell tumours of the ovary for somatic mutations in LKB1. No variants were detected in any of the adenocarcinomas. Two mutations were detected in one of the granulosa cell tumours: a mis-sense mutation affecting the putative 'start' codon (ATG --> ACG, M1T); and a silent change in exon 7 (CTT --> CTA, leucine). Like BRCA1 and BRCA2, therefore, it appears that LKB1 mutations can cause ovarian tumours when present in the germline, but occur rarely in the soma. The allele loss on 19p13.3 in ovarian cancers almost certainly targets a different gene from LKB1.
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PMID:Allele loss and mutation screen at the Peutz-Jeghers (LKB1) locus (19p13.3) in sporadic ovarian tumours. 1038 80

Patients with Peutz-Jeghers' syndrome (PJS) develop hamartomatous gastrointestinal polyps and characteristic pigmentation, as a result of germline mutations in the LKB1 gene. The hamartomas in PJS were long considered to be without malignant potential. There is, however, accumulating epidemiological evidence to suggest that PJS predisposes to cancers at several different sites (colon, pancreas, breast, ovary, testis, and cervix), although large enough patient samples are rarely available to prove this. Allelic imbalance [allele loss, loss of heterozygosity (LOH)] has previously been reported in a small number of PJS polyps, suggesting that LKB1 acts as a tumour suppressor in these tumours. This study confirms allelic loss at LKB1 in PJS polyps and shows that LOH also occurs in cancers of the colon, breast, and cervix in PJS patients. Allele loss was additionally found in a colonic adenoma from a PJS patient, strongly suggesting the existence of a hamartoma-(adenoma)-carcinoma sequence in tumourigenesis. These results provide molecular evidence that PJS patients are predisposed to cancers at several sites, as a direct result of selection for loss of the 'wild-type' LKB1 allele in tumours. Given the rare involvement of LKB1 in sporadic cancers, these data also suggest that the indirect effect on cancer risk (or 'bystander effect') proposed for hamartomas in juvenile polyposis does not apply to carcinomas in PJS.
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PMID:Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence. 1039 31

The LKB1/STK11 serine/threonine kinase is mutated in Peutz-Jeghers' syndrome and acts as a tumour suppressor. Using northern blotting and RT-PCR, LKB1 has been reported to be expressed widely in human adult tissues, although in Xenopus the expression of its homologue, XEEK1, is apparently restricted to early embryogenesis. In situ hybridization has been used to detect and localize LKB1 mRNA in a variety of adult and fetal tissues and tumours. The results show that LKB1 expression is widespread, but predominant in epithelia and in the seminiferous tubules of the testis. Expression is higher in fetal than in adult tissues. Expression also appears to be higher in many malignant tumours than in normal tissues or benign lesions, although some cancers have lost LKB1 expression, quite possibly as part of the process of tumourigenesis. These data are consistent with a widespread functional role for LKB1 in tissues of most types, and with a role for LKB1 in the pathogenesis of some sporadic cancers. LKB1 expression may primarily be related to the rate of cell replication.
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PMID:In situ analysis of LKB1/STK11 mRNA expression in human normal tissues and tumours. 1100 96

Peutz-Jeghers syndrome is an inherited cancer syndrome, which results in a greatly increased risk of developing tumours in those affected. The causative gene encodes a nuclear-localized protein kinase, termed LKB1, which is predicted to function as a tumour suppressor. The mechanism by which LKB1 is regulated in cells is not known, and nor have any of its physiological substrates been identified. Recent studies have demonstrated that LKB1 is phosphorylated in cells. As a first step towards identifying the roles that phosphorylation of LKB1 play, we have mapped the residues that are phosphorylated in human embryonic kidney (HEK)-293 cells, as well as the major in vitro autophosphorylation sites. We demonstrate that LKB1 expressed in HEK-293 cells, in addition to being phosphorylated at Ser(431), a previously characterized phosphorylation site, is also phosphorylated at Ser(31), Ser(325) and Thr(366). Incubation of wild-type LKB1, but not a catalytically inactive mutant, with manganese-ATP in vitro resulted in the phosphorylation of LKB1 at Thr(336) as well as at Thr(366). We were unable to detect autophosphorylation at Thr(189), a site previously claimed to be an LKB1 autophosphorylation site. A catalytically inactive mutant of LKB1 was phosphorylated at Ser(31) and Ser(325) in HEK-293 cells to the same extent as the wild-type enzyme, indicating that LKB1 does not phosphorylate itself at these residues. We show that phosphorylation of LKB1 does not directly affect its nuclear localization or its catalytic activity in vitro, but that its phosphorylation at Thr(336), and perhaps to a lesser extent at Thr(366), inhibits LKB1 from suppressing cell growth.
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PMID:Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome. 1185 58

Germline mutations in LKB1 (also known as STK11) are associated with Peutz-Jeghers syndrome (PJS), a disorder with predisposition to gastrointestinal polyposis and cancer. PJS polyps are unusual neoplasms characterized by marked epithelial and stromal overgrowth but have limited malignant potential. Here we show that Lkb1(+/-) mice develop intestinal polyps identical to those seen in individuals affected with PJS. Consistent with this in vivo tumour suppressor function, Lkb1 deficiency prevents culture-induced senescence without loss of Ink4a/Arf or p53. Despite compromised mortality, Lkb1(-/-) mouse embryonic fibroblasts show resistance to transformation by activated Ha-Ras either alone or with immortalizing oncogenes. This phenotype is in agreement with the paucity of mutations in Ras seen in PJS polyps and suggests that loss of Lkb1 function as an early neoplastic event renders cells resistant to subsequent oncogene-induced transformation. In addition, the Lkb1 transcriptome shows modulation of factors linked to angiogenesis, extracellular matrix remodelling, cell adhesion and inhibition of Ras transformation. Together, our data rationalize several features of PJS polyposis--notably its peculiar histopathological presentation and limited malignant potential--and place Lkb1 in a distinct class of tumour suppressors.
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PMID:Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. 1222 50

Peutz-Jeghers Syndrome (PJS) is thought to be caused by mutations occurring in the widely expressed serine/threonine protein kinase named LKB1/STK11. Recent work has led to the identification of four mutants (R304W, I177N, K175-D176del, L263fsX286) and two novel aberrant LKB1/STK11 cDNA isoforms (r291-464del, r485-1283del) in a group of PJS Italian patients. Three of the four mutations only change 1 or 2 amino acids in the LKB1/STK11 catalytic domain. Here we demonstrate that all six LKB1/STK11 variants analysed are completely inactive in vitro as they were unable to autophosphorylate at Thr336, the major LKB1/STK11 autophosphorylation site, and to phosphorylate the p53 tumour suppressor protein. We also show that 5 out of the 6 variants are entirely localised in the nucleus in contrast to the wild type LKB1/STK11, which is detected in both the nucleus and cytoplasm. Finally we demonstrate that all 6 LKB1/STK11 variants, in contrast to wild type LKB1/STK11, are unable to suppress the growth of melanoma G361 cells. Taken together, these results demonstrate that the LKB1 mutations investigated in this study lead to the loss of serine/threonine kinase activity and are therefore likely to be the primary cause of PJS development in the patients that they were isolated from.
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PMID:Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients. 1255 71

LKB1 is a serine-threonine protein kinase mutated in patients with an autosomal dominantly inherited cancer syndrome predisposing to multiple benign and malignant tumours, termed Peutz-Jeghers syndrome. Since its discovery in 1998, much research has focused on identification and characterisation of its cellular roles and analysing how LKB1 might be regulated. In this review we discuss exciting recent advances indicating that LKB1 functions as a tumour suppressor perhaps by controlling cell polarity. We also outline the current understanding of the molecular mechanisms by which LKB1 is regulated in vivo, through interaction with other proteins as well as by protein phosphorylation and prenylation.
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PMID:LKB1, a protein kinase regulating cell proliferation and polarity. 1282 53

Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz-Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27-73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.
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PMID:Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. 1286 22

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal-dominant inherited disorder characterised by multiple gastrointestinal hamartomatous polyps, melanin spots of the oral mucosa and digits, and an increased risk for various neoplasms. The PJS results from germline alterations of the STK11/LKB1 tumour suppressor gene, located on 19p13.3, and encoding a serine/threonine kinase. The detection of STK11 germline mutations, in only 50-70% of PJS families, has suggested a genetic heterogeneity of the disease. We report the case of a family with typical features of PJS, including gastrointestinal hamartomatous, breast cancers and melanin spots of the oral mucosa. Quantitative multiplex PCR of short fluorescent fragments (QMPSF) of the 19p13 region allowed us to identify an approximately 250 kb heterozygous deletion removing entirely the STK11 locus. This report, which constitutes the first description of a complete germline deletion of STK11, shows that the presence of such large genomic deletions should be considered in PJS families without detectable point mutations of STK11.
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PMID:Complete germline deletion of the STK11 gene in a family with Peutz-Jeghers syndrome. 1497 Aug 44

Mutations in the lkb1 gene are found in Peutz-Jeghers syndrome (PJS), with loss of heterozygosity or somatic mutations at the lkb1 locus, suggesting the gene product, the serine/threonine kinase LKB1, may function as a tumour suppressor. Patients with PJS are at a greater risk of developing cancers of epithelial tissue origin. It is widely accepted that the presence of hamartomatous polyps in PJS does not in itself lead to the development of malignancy. The signalling mechanisms that lead to these PJS related malignancies are not well understood. However, it is evident from the recent literature that LKB1 is a multitasking kinase, with unlimited potential in orchestrating cell activity. Thus far, LKB1 has been found to play a role in chromatin remodelling, cell cycle arrest, Wnt signalling, cell polarity, and energy metabolism, all of which may require the tumour suppressor function of this kinase and/or its catalytic activity.
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PMID:LKB1, the multitasking tumour suppressor kinase. 1562 75


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