Vascular Abnormalities and Deregulation of
            <i>VEGF</i>
            in
            <i>Lkb1</i>
            -Deficient Mice

Ylikorkala, Antti; Rossi, Derrick J.; Korsisaari, Nina; Luukko, Keijo; Alitalo, Kari; Henkemeyer, Mark; Mäkelä, Tomi P.

doi:10.1126/science.1062074

Cited by 265 publications

(243 citation statements)

References 15 publications

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“…The Stk11/Lkb1 protein is ubiquitously expressed in all human fetal and adult tissues (Rowan et al, 2000). Homozygous deletion of STK11/LKB1 in mice leads to embryonic lethality at midgestation (E11.0), indicating that STK11/LKB1 plays an important role in embryogenesis (Ylikorkala et al, 2001;Jishage et al, 2002). Interestingly, most of the STK11/LKB1 þ /À mice developed intestinal polyps by the age of 45 weeks, identical to those observed in patients with PJS (Bardeesy et al, 2002;Jishage et al, 2002;Nakau et al, 2002).…”

mentioning

confidence: 75%

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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confidence: 75%

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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“…Homozygous loss of Lkb1 is embryonically lethal, whereas mice with a heterozygous deletion are tumor prone, showing an increased incidence of spontaneous tumor formation as well as increased susceptibility to toxicity-induced carcinogenesis (Ylikorkala et al, 2001;Jishage et al, 2002;Miyoshi et al, 2002;Gurumurthy et al, 2008). Moreover, Lkb1 þ /À mice develop hamartomatous polyps in the stomach and intestines, but, similar to their human counterparts, these polyps appear to lack or have only low malignant potential (Jishage et al, 2002;Miyoshi et al, 2002).…”

Section: Nf1mentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…Inactivating homozygous mutation of Lkb1 in mice is embryonically lethal with mice dying midgestation, demonstrating neural tube defects and vascular abnormalities (Ylikorkala et al, 2001). Heterozygous mice are viable but develop hamartomatous polyps, characteristic of PJS, with high penetrance (Bardeesy et al, 2002;Jishage et al, 2002;Miyoshi et al, 2002;Rossi et al, 2002).…”

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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Vascular Abnormalities and Deregulation of VEGF in Lkb1 -Deficient Mice

Cited by 265 publications

References 15 publications

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

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

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

LKB1; linking cell structure and tumor suppression

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