Loss of anchorage in checkpoint-deficient cells increases genomic instability and promotes oncogenic transformation.
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.
Cremona
Catherine A
CA
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.
Lloyd
Alison C
AC
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
D016213:Cyclins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases
Mol Cell Biol. 2003 Apr;23(7):2530-42
12640134
Mol Cancer Res. 2004 Feb;2(2):96-104
14985466
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6223-8
17384149
Trends Cell Biol. 2008 Jul;18(7):347-52
18514521
Nature. 1999 Jul 29;400(6743):464-8
10440377
Curr Opin Genet Dev. 2001 Feb;11(1):48-53
11163150
Mol Cell Biol. 2006 Jun;26(11):4201-13
16705171
Mol Cell. 2003 Apr;11(4):997-1008
12718885
Science. 2008 Mar 7;319(5868):1352-5
18323444
Cell. 2000 Jan 7;100(1):57-70
10647931
Science. 1993 Dec 3;262(5139):1572-5
8248807
Science. 2001 Feb 2;291(5505):872-5
11157166
Nat Rev Cancer. 2008 Oct;8(10):799-806
18756287
Exp Cell Res. 2001 Mar 10;264(1):169-84
11237532
Nature. 2006 Nov 30;444(7119):638-42
17136094
Annu Rev Pathol. 2006;1:119-50
18039110
Trends Pharmacol Sci. 2008 Jan;29(1):16-21
18054800
Cell. 2007 Jan 26;128(2):269-80
17254966
Cancer Cell. 2002 Aug;2(2):103-12
12204530
Cancer Res. 2006 Nov 1;66(21):10258-63
17079443
Nat Cell Biol. 2006 Jan;8(1):37-45
16327781
Mol Biol Cell. 1999 Oct;10(10):3197-204
10512860
Nature. 2005 Apr 14;434(7035):864-70
15829956
J Cell Biol. 1994 Feb;124(4):619-26
8106557
Nat Rev Cancer. 2002 Dec;2(12):910-7
12459729
Cancer Cell. 2008 Jan;13(1):58-68
18167340
N Engl J Med. 2002 Nov 14;347(20):1593-603
12432047
Oncogene. 1997 Aug 7;15(6):629-37
9264403
Jpn J Cancer Res. 1998 Feb;89(2):110-5
9548436
Cell. 1974 Dec;3(4):355-9
4442124
J Cell Biol. 1996 Apr;133(2):391-403
8609171
Oncogene. 2007 Sep 20;26(43):6307-18
17452985
Cell. 1996 May 31;85(5):721-32
8646780
J Cell Sci. 2001 Jul;114(Pt 14):2553-60
11683383
Cell Div. 2008 Jan 22;3:3
18211690
Nature. 2006 Nov 30;444(7119):633-7
17136093
Curr Biol. 1996 Apr 1;6(4):474-83
8723352
Nature. 2004 Nov 18;432(7015):338-41
15549096
J Biol Chem. 2007 Aug 17;282(33):23867-77
17556357
Science. 1996 Jan 26;271(5248):499-502
8560263
Genes Dev. 2001 Feb 15;15(4):398-403
11230148
Nature. 2005 Apr 14;434(7035):907-13
15829965
Nat Rev Cancer. 2008 Apr;8(4):253-67
18354415