title: Loss of anchorage in checkpoint-deficient cells increases genomic instability and promotes oncogenic transformation.
abstract: Mammalian cells generally require both mitogens and anchorage signals in order to proliferate. An important characteristic of many tumour cells is that they have lost this anchorage-dependent cell-cycle checkpoint, allowing them to proliferate without signals provided by their normal microenvironment. In the absence of anchorage signals from the extracellular matrix, many cell types arrest cell-cycle progression in G1 phase as a result of Rb-dependent checkpoints. However, despite inactivation of p53 and Rb proteins, SV40LT-expressing cells retain anchorage dependency, suggesting the presence of an uncharacterised cell-cycle checkpoint, which can be overridden by coexpression of oncogenic Ras. We report here that, although cyclin-CDK complexes persisted in suspension, proliferation was inhibited in LT-expressing cells by the CDK inhibitor p27(Kip1) (p27). Interestingly, this did not induce a stable arrest, but aberrant cell-cycle progression associated with stalled DNA replication, rereplication and chromosomal instability, which was sufficient to increase the frequency of oncogenic transformation. These results firstly indicate loss of anchorage in Rb- and p53-deficient cells as a novel mechanism for promotion of genomic instability; secondly suggest that anchorage checkpoints that protect normal cells from inappropriate proliferation act deleteriously in Rb- and p53-deficient cells to promote tumourigenesis; and thirdly indicate caution in the use of CDK inhibitors for cancer treatment.
authors.affiliation: Department of Cell and Developmental Biology and 3The UCL Cancer Institute, MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Cremona
authors.forename: Alison C
authors.initials: AC
authors.lastname: Lloyd
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D051381:Rats; D016196:S Phase
chemical_list: D016213:Cyclins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases
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