Abstract
The Wnt signalling cascade plays an important role
during embryonic patterning and cell fate determination
and is highly conserved throughout evolution.
Factors of the TCF/LEF HMG domain family (Tcfs) are
the downstream effectors of this signal transduction
pathway. Upon Wnt signalling, a cascade is initiated
that results in the translocation of βcatenin to the
nucleus, where it interacts with Tcf to generate a transcriptionally
active complex. This bipartite transcription
factor is targeted to the upstream regulatory regions
of Tcf target genes. In the absence of Wnt
signals, βcatenin is degraded in the cytoplasm via
the ubiquitinproteasome pathway. Several proteins
are instrumental in achieving this tight regulation of
βcatenin levels in the cell, including adenomatous
polyposis coli (APC), GSK3 β, and Axin/Conductin.
Deregulation of the Wnt signalling pathway is implicated
in several forms of cancer, such as colon carcinoma
and melanoma. This deregulation is achieved
via mutation of APC, βcatenin or Axin, resulting in elevated
βcatenin levels and the presence of constitutively
active Tcfβcatenin complexes in the nucleus.
The accompanying inappropriate activation of target
genes is considered to be a critical, early event in this
carcinogenesis.
In addition to regulating βcatenin levels, normal
healthy cells have evolved a second level of regulation,
by manipulating the activity of the Tcf proteins
themselves. In the absence of Wnt signalling, Tcf
complexes with several transcriptional repressor
proteins ensuring active repression of Tcf target
genes. In this review the dual role of Tcf proteins in the
Wnt signalling cascade will be discussed.
Epigenetic transgenerational inheritance, Gametogenesis and Germline Development