Wnt signaling and cancer

  1. Paul Polakis1
  1. Department of Molecular Oncology, Genentech Inc., South San Francisco, California 94080 USA

This extract was created in the absence of an abstract.

The regulation of cell growth and survival can be subverted by a variety of genetic defects that alter transcriptional programs normally responsible for controlling cell number. High throughput analysis of these gene expression patterns should ultimately lead to the identification of minimal expression profiles that will serve as common denominators in assigning a cancer to a given category. In the course of defining the common denominators, though, we should not be too surprised to find that cancers within a single category may nevertheless exhibit seemingly disparate genetic defects. The wnt pathway has already provided an outstanding example of this. We now know of three regulatory genes in this pathway that are mutated in primary human cancers and several others that promote experimental cancers in rodents (Fig. 1). In all of these cases the common denominator is the activation of gene transcription by β-catenin. The resulting gene expression profile should provide us with a signature common to those cancers carrying defects in the wnt pathway. In this review, the wnt pathway will be covered from the perspective of cancer, with emphasis placed on molecular defects known to promote neoplastic transformation in humans and in animal models.

Figure 1.

Oncogenes and tumor suppressors in the wnt signaling pathway. Lines ending with arrows or bars indicate activating or inhibitory effects, respectively. Green and red indicate proto-oncogenic and tumor suppressive activity, respectively, in human cancer or transgenic animals. Definition of the genes and the basis for their activities are described in the text.

The wnt signaling mechanism

The model illustrated in Figure 2 is a proposed mechanism for wnt signaling and is based on the following literature. Signaling is initiated by the secreted wnt proteins, which bind to a class of seven-pass transmembrane receptors encoded by the frizzled genes (Bhanot et al. 1996; Yang-Snyder et al. 1996; He …

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