A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma.
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.
Qiu
W
W
Department of Otolaryngology and Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Schönleben
F
F
Thaker
H M
HM
Goggins
M
M
Su
G H
GH
D000091162:AMP-Activated Protein Kinase Kinases; D019943:Amino Acid Substitution; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D018095:Germ-Line Mutation; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007438:Introns / Q000235:genetics; D019656:Loss of Heterozygosity; D020125:Mutation, Missense / Q000235:genetics*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases