A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma
Open Access
- 16 January 2006
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 25 (20), 2937-2942
- https://doi.org/10.1038/sj.onc.1209325
Abstract
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.Keywords
This publication has 34 references indexed in Scilit:
- LKB1 (XEEK1) regulates Wnt signalling in vertebrate developmentNature, 2003
- Regulation of the Wnt signalling component PAR1A by the Peutz–Jeghers syndrome kinase LKB1Oncogene, 2003
- Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinasesProceedings of the National Academy of Sciences of the United States of America, 2003
- Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patientsHuman Mutation, 2003
- Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformationNature, 2002
- Induction of cyclooxygenase-2 in a mouse model of Peutz–Jeghers polyposisProceedings of the National Academy of Sciences of the United States of America, 2002
- Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice.2002
- Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung.2002
- Role of Lkb1 , the causative gene of Peutz–Jegher's syndrome, in embryogenesis and polyposisProceedings of the National Academy of Sciences of the United States of America, 2002
- Germline and Somatic Mutations of the STK11/LKB1 Peutz-Jeghers Gene in Pancreatic and Biliary CancersThe American Journal of Pathology, 1999