Mutation analysis of DKK1 and in vivo evidence of predominant p53-independent DKK1 function in gliomas.
DKK1 protein belongs to a family of inhibitors of the Wnt/beta1-catenin signaling pathway. Sporadic mutations affecting almost each major player of the Wnt/beta1-catenin pathway have been described in a variety of human carcinomas. DKK1 translation can be induced by p53, thereby linking TP53 and Wnt/beta1-catenin signaling pathways. These findings raise questions in regard to human gliomas, which similar to carcinomas carry a high rate of mutations in TP53. To analyze DKK1 for its role in initiation or progression, we screened a series of 73 brain tumors for structural alterations in the entire coding sequence by single-strand conformation polymorphism and direct sequencing. While several sequence variants were detected, there were no obvious mutations affecting DKK1. Further, we analyzed the prevalence of mRNA from TP53, DKK1 and CTNNB1 and of p53 and beta1-catenin protein in a series of human gliomas with and without mutations in TP53. Transcription and expression of CTNNB1/beta1-catenin and DKK1 proved to be independent of TP53/p53. These data support in vivo function of DKK1, independent of p53, in human gliomas with no major impact on their pathogenesis.
Mueller
Wolf
W
Department of Neuropathology, Charité, Humboldt University, Augustenburger Platz 1, 13353, Berlin, Germany.
Lass
Ulrike
U
Wellmann
Sven
S
Kunitz
Frank
F
von Deimling
Andreas
A
D015139:Blotting, Southern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013194:Staining and Labeling / Q000379:methods; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin