p27kip1 deficiency impairs G2/M arrest in response to DNA damage, leading to an increase in genetic instability.
p27(kip1) is a cyclin-dependent kinase inhibitor and a tumor suppressor. In some tumors, p27 suppresses tumor growth by inhibition of cell proliferation. However, this is not universally observed, implying additional mechanisms of tumor suppression by p27. p27-deficient mice are particularly susceptibility to genotoxin-induced tumors, suggesting a role for p27 in the DNA damage response. To test this hypothesis, we measured genotoxin-induced mutations and chromosome damage in p27-deficient mice. Both p27(+/-) and p27(-/-) mice displayed a higher N-ethyl-N-nitrosourea-induced mutation frequency in the colon than p27(+/+) littermates. Furthermore, cells from irradiated p27-deficient mice exhibited a higher number of chromatid breaks and showed modestly increased micronucleus formation compared to cells from wild-type littermates. To determine if this mutator phenotype was related to the cell cycle-inhibitory function of p27, we measured cell cycle arrest in response to DNA damage. Both normal and tumor cells from p27-deficient mice showed impaired G(2)/M arrest following low doses of ionizing radiation. Thus, p27 may inhibit tumor development through two mechanisms. The first is by reducing the proliferation of cells that have already sustained an oncogenic lesion. The second is by transient inhibition of cell cycle progression following genotoxic insult, thereby minimizing chromosome damage and fixation of mutations.
Payne
Shannon R
SR
Fred Hutchinson Cancer Research Center C1-015, 1100 Fairview Ave. N., Seattle, WA 90109-1024, USA.
Zhang
Shulin
S
Tsuchiya
Karen
K
Moser
Russell
R
Gurley
Kay E
KE
Longton
Gary
G
deBoer
Johan
J
Kemp
Christopher J
CJ
D000818:Animals; D002455:Cell Division / Q000235:genetics / Q000528:radiation effects; D002842:Chromatids / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D016195:G2 Phase / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D009153:Mutagens; D050760:Cyclin-Dependent Kinase Inhibitor p27