Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma

Guldberg, Per; Straten, Per thor; Ahrenkiel, Vibeke; Seremet, Tina; Kirkin, Alexei F.; Zeuthen, Jesper

doi:10.1038/sj.onc.1202486

Cited by 128 publications

(86 citation statements)

References 23 publications

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“…Mutational analysis across a range of sporadic tumors has identified loss of function LKB1 mutations most frequently in non-small cell lung carcinomas; between 5 and 17% of cases depending on the population studied (Sanchez-Cespedes et al, 2002;Ji et al, 2007;Koivunen et al, 2008). Somatic inactivating mutations in LKB1 have also been reported in approximately 5% of pancreatic cancers and melanomas, and in single specimens of prostate cancer and cervical cancer (Avizienyte et al, , 1999Bignell et al, 1998;Wang et al, 1998;Guldberg et al, 1999;Rowan et al, 1999;Su et al, 1999;Forster et al, 2000;Ikediobi et al, 2006). Overall, the incidence of LKB1 mutation in sporadic cancers, other than lung cancer, appears low despite the high penetrance of carcinomas associated with PJS.…”

Section: Peutz-jeghers Syndrome and Human Cancer Geneticsmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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Section: Peutz-jeghers Syndrome and Human Cancer Geneticsmentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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“…Biallelic inactivation of the STK11/LKB1 gene is also observed in a small percentage of sporadic cancers Chen et al, 1999;Guldberg et al, 1999). For example, we previously reported germline and somatic mutations of the STK11/ LKB1 gene in 4-6% of pancreatic and biliary cancers (Su et al, 1999).…”

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confidence: 94%

A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma

et al. 2006

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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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“…LKB1 was first recognized as a tumor-suppressor gene because its mutations cause Peutz-Jeghers syndrome, characterized by gastrointestinal hamartoma with an increased cancer risk (Giardiello et al, 2000;van Lier et al, 2010). This gene was later found to be a target for mutational inactivation in human malignancies including non-small cell lung carcinoma (Sanchez-Cespedes et al, 2002;Carretero et al, 2004;Ji et al, 2007;Matsumoto et al, 2007;Makowski and Hayes, 2008;Komiya et al, 2010;Mahoney et al, 2009), cervical carcinoma (Wingo et al, 2009), melanoma (Guldberg et al, 1999;Rowan et al, 1999) and others (Sanchez-Cespedes, 2007). The LKB1 gene encodes a serine/threonine kinase essential for the activation of AMPK (AMP-activated protein kinase) and 12 AMPK-related kinases; thus, it regulates multiple signaling pathways in cell growth, cell polarity and metabolism (Hezel and Bardeesy, 2008;Shackelford and Shaw, 2009;Luo et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

et al. 2011

Oncogene

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LKB1 is a tumor susceptibility gene for the Peutz-Jeghers cancer syndrome and is a target for mutational inactivation in sporadic human malignancies. LKB1 encodes a serine/threonine kinase that has critical roles in cell growth, polarity and metabolism. A novel and important function of LKB1 is its ability to regulate the phosphorylation of CREB-regulated transcription co-activators (CRTCs) whose aberrant activation is linked with oncogenic activities. However, the roles and mechanisms of LKB1 and CRTC in the pathogenesis of esophageal cancer have not been previously investigated. In this study, we observed altered LKB1-CRTC signaling in a subset of human esophageal cancer cell lines and patient samples. LKB1 negatively regulates esophageal cancer cell migration and invasion in vitro. Mechanistically, we determined that CRTC signaling becomes activated because of LKB1 loss, which results in the transcriptional activation of specific downstream targets including LYPD3, a critical mediator for LKB1 loss-of-function. Our data indicate that de-regulated LKB1-CRTC signaling might represent a crucial mechanism for esophageal cancer progression.

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Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma

Cited by 128 publications

References 23 publications

LKB1; linking cell structure and tumor suppression

LKB1; linking cell structure and tumor suppression

A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

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