Trends in Cell Biology
ReviewSignalling networks that cause cancer
Section snippets
Ras: concerted pathways leading to cancer
Ras proteins activate multiple signalling pathways (summarized in Fig. 1). Ras binds to at least three types of effector protein: kinases of the Raf family, phosphoinositide (PI) 3-kinases and RalGDS proteins. Several other candidate effector proteins have been identified, such as Rin1 and AF6, but their biological functions are not yet known1. The molecular mechanisms that lead to activation of Ras effectors are complicated and unclear, and the downstream consequences of activation are more
APC: more of the same?
Mutational inactivation of the gene encoding APC occurs in the majority of human colon cancers and leads to accumulation of β-catenin. Many of the remaining colon cancers, as well as other types of cancer, have mutations in β-catenin itself, at sites that make the protein resistant to APC-directed destruction17. β-catenin binds to and activates transcription factors of the T-cell factor (TCF)/lymphoid enhancer factor (LEF) family, a signalling event that occurs normally in response to Wnt
When pathways collide
Expression of cyclin D1 is regulated by activated Ras, forging a potential link from growth-factor signalling to cell-cycle progression through G1 to S phase. Ras has multiple effects on cyclin D1: the Raf–MAPK branch of the Ras pathway regulates transcription of the gene encoding cyclin D124 and the PI 3-kinase branch affects stability of the cyclin D1 protein, through the action of PKB and of glycogen synthase kinase 3β25. Perhaps these distinct effects provide the basis of synergy between
Functional steps into cancer
In the current view of multistep carcinogenesis, each new mutational step leads to a clonal expansion of cells bearing the new mutation: in this way, the probability that multiple mutations occur in the same cell is greatly increased. Without this clonal expansion of mutant cells, the chances of accumulating several very rare events in the same cell becomes vanishingly small. The strong interdependence of oncogenic events discussed here constrains this model and strongly suggests that mutations
Concluding remarks
Our current view of the stepwise progression of cancer, most elegantly illustrated by the development of colorectal cancer (see article by Cahill et al. in this issue), contains unexpectedly deterministic elements, in which mutations in pathways that once seemed distinct strongly influence subsequent mutations, either by providing a more permissive cellular environment or by creating the need for further genetic changes for cell survival. This view has been created by projecting our functional
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