Gene: WNT-1 maps to 12q13, a chromosomal region frequently rearranged in human tumours.
mRNA: size: ? kb.
Protein: formerly known as Int-1 (Nusse R. et al., 1991), Wnt-1 is a secreted glycoprotein acting as an extracellular ligand capable of promoting mitogenesis. Wnt-1 appears to signal via a unique pathway, thought to be initiated by interaction of Wnt-1 with a member of the Frizzled family of seven-transmembrane receptors, leading to the stabilization of a cytosolic pool of
ß-catenin (Cadigan K.M. and Nusse R., 1997).
Cell lines:
- Wnt-1 expression in the mouse mammary epithelial cell lines RAC311 and C57MG was shown to induce stabilization of cytosolic
beta-catenin and morphological transformation. Expression of Wnt-1 in these cells caused transcriptional up-regulation of the
cyclooxygenase-2 gene, resulting in increased levels of
cyclooxygenase-2 mRNA and protein. Prostaglandin E2 production was increased as a consequence of the elevated
cyclooxygenase-2 activity and could be decreased by treatment with a selective
cyclooxygenase-2 inhibitor.
Cyclooxygenase-2 thus appears to be a common downstream target for APC mutation and Wnt-1 expression (Howe L.R. et al., 1999).
Tumors:
- Wnt-1 was first identified as target for insertional activation by the mouse mammary tumor virus (MMTV) in mammary carcinomas. Ectopic expression of Wnt-1 under the control of a MMTV promoter leads to extensive mammary hyperplasia and subsequent generation of adenocarcinomas in mice (Tsukamoto A.S. et al., 1988).
- Observations in male and female mice suggested that ectopic expression of the Wnt-1 proto-oncogene can induce mammary hyperplasia and tumorigenesis in the absence of
ER-alpha (Bocchinfuso W.P. et al., 1999).
Arheden K. et al. (1988) Chromosome localization of the human oncogene INT1 to 12q13 by in situ hybridization. Cytogenet. Cell Genet. 47, 86-87.
Bocchinfuso W.P. et al. (1999) A mouse mammary tumor virus-Wnt-1 transgene induces mammary gland hyperplasia and tumorigenesis in mice lacking
estrogen receptor-alpha. Cancer Res. 59, 1869-1876.
Cadigan K.M. and Nusse R. (1997) Wnt signaling: a common theme in animal development. Genes Dev. 11, 3286-3305.
Howe L.R. et al. (1999) Transcriptional activation of
cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells. Cancer Res. 59, 1572-1577.
Nusse R. et al. (1991) A new nomenclature for int-1 and related genes: the Wnt gene family. (Letter) Cell 64, 231-232.
Tsukamoto A.S. et al. (1988) Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55, 619-625.
van't Veer L.J. et al. (1984) Molecular cloning and chromosomal assignment of the human homolog of int-1, a mouse gene implicated in mammary tumorigenesis. Molec. Cell. Biol. 4, 2532-2534.
van Ooyen A. et al. (1985) The nucleotide sequence of the human int-1 mammary oncogene; evolutionary conservation of coding and non-coding sequences. EMBO J. 4, 2905-2909.
