MUC1 cytoplasmic domain coactivates Wnt target gene transcription and confers transformation

Cancer Biol Ther. Nov-Dec 2003;2(6):702-6.

Abstract

The DF3/MUC1 mucin-like transmembrane oncoprotein is overexpressed by most human carcinomas. The MUC1 cytoplasmic domain (CD) binds directly to the Wnt effector, beta-catenin, and colocalizes with beta-catenin in the nucleus; however, the nuclear function of MUC1 is unknown. The present results demonstrate that MUC1 coactivates transcription of beta-catenin-Tcf-binding sites in the pTOPFLASH reporter. Activation of transcription was abrogated by expression of MUC1 with a Y-46->F mutation in the CD that attenuates binding of MUC1 and beta-catenin. We also show that transcription of the Wnt responsive cyclin D1 promoter is activated by MUC1, but not MUC1(Y46F), and that the cyclin D1 gene is upregulated in MUC1-positive cells. In concert with these results, MUC1-induced anchorage-independent growth and tumorigenicity were also abrogated by mutating MUC1 at the Y-46 site. These findings support a model in which the MUC1 functions as a transforming protein by coactivating transcription of Wnt target genes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Adhesion / genetics
  • Cell Nucleus / metabolism
  • Cell Transplantation
  • Clone Cells
  • Cyclin D1 / genetics
  • Cytoplasm / chemistry
  • Cytoskeletal Proteins
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • HCT116 Cells
  • Humans
  • Luciferases / metabolism
  • Mice
  • Mice, Nude
  • Mucin-1 / chemistry
  • Mucin-1 / genetics
  • Mucin-1 / metabolism*
  • Mutation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Structure, Tertiary*
  • Proto-Oncogene Proteins / metabolism*
  • Trans-Activators
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Transcriptional Activation*
  • Up-Regulation
  • Wnt Proteins
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Mucin-1
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Wnt Proteins
  • beta Catenin
  • Cyclin D1
  • Luciferases