title: STK10 missense mutations associated with anti-apoptotic function.
abstract: Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma with a 5-year overall survival rate of <30%. To identify carcinogenesis-related genes in PTCL, we conducted high-throughput resequencing of target-captured cDNA in a PTCL specimen, revealing a total of 19 missense mutations among 18 independent genes. One of such substitutions, c.2201G>A in STK10 cDNA, replaces an arginine residue to a histidine (R634H) in the encoded protein. Of note, while wild-type STK10 suppresses NF-κB activity and potentiates dexamethasone-induced apoptosis, the R634H change significantly decreases such pro-apoptotic activity. This c.2201G>A change of STK10 was also identified in another PTCL specimen, but now registered as a single nucleotide polymorphism in the latest dbSNP database. Furthermore, other somatic mutations of STK10 have been reported, and we now reveal that some of them (L85P and K277E) have more profound anti-apoptotic effects compared to R634H. These results suggest that STK10 functions as a tumor suppressor gene, and that dysfunction of STK10 activity either through polymorphism or somatic mutations may confer anti-apoptotic effects contributing to carcinogenesis.
authors.affiliation: Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Fukumura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Masahito
authors.initials: M
authors.lastname: Kawazu
authors.forename: Eirin
authors.initials: E
authors.lastname: Sai
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Naoya
authors.initials: N
authors.lastname: Nakamura
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Mizuo
authors.initials: M
authors.lastname: Ando
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueno
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C474806:STK10 protein, human