title: Genetic alterations of the TGF-beta signaling pathway in colorectal cancer cell lines: a novel mutation in Smad3 associated with the inactivation of TGF-beta-induced transcriptional activation.
abstract: To investigate genetic alterations involved in the TGF-beta signaling pathway in colorectal cancer, we assayed DNA synthesis rates after treating TGF-beta and checked for genetic alterations in TGF-betaRII, TGF-betaRI, Smad2, Smad3, and Smad4 in 12 colorectal cancer cell lines. Eleven lines, except SNU-61, show no significant change in DNA synthesis rate after TGF-beta treatment. In these 11 lines, several mutations were found in genes involved in the TGF-beta signaling pathway: (i) frameshift deletions in the poly(A)(10) tract of the TGF-betaRII gene in SNU-407, SNU-769A, SNU-769B, and SNU-1047 cell lines, (ii) a missense mutation of Smad2 (R321Q) in SNU-81, (iii) two missense mutations in TGF-betaRI (R487W in SNU-175 and A202V in SNU-1040), and (iv) a monoallelic loss at the Smad4 locus in three cell lines. Interestingly, a missense mutation (R373H) in Smad3 gene was found in SNU-769A. To our knowledge, this is the first report of Smad3 mutation in human malignancy. This mutation was found to result in the inhibition of translocation of Smad3 protein to the nucleus and a reduction in the activity of Smad3 during TGF-beta-induced transcriptional activation. These results indicate that the majority of cell lines, which are insensitive to TGF-beta, have alterations in genes involved in the TGF-beta signaling pathway in colorectal cancer cell lines.
authors.affiliation: Laboratory of Cell Biology, Korean Cell Line Bank, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea.
authors.forename: Ja-Lok
authors.initials: JL
authors.lastname: Ku
authors.forename: Seok-Hee
authors.initials: SH
authors.lastname: Park
authors.forename: Kyong-Ah
authors.initials: KA
authors.lastname: Yoon
authors.forename: Young-Kyoung
authors.initials: YK
authors.lastname: Shin
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.forename: Hio-Chung
authors.initials: HC
authors.lastname: Kang
authors.forename: Il-Jin
authors.initials: IJ
authors.lastname: Kim
authors.forename: Inn-Oc
authors.initials: IO
authors.lastname: Han
authors.forename: Jae-Gahb
authors.initials: JG
authors.lastname: Park
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D017931:DNA Primers; D016368:Frameshift Mutation; D006801:Humans; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D051900:Smad3 Protein / Q000235:genetics*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta