p53 and SCFFbw7 cooperatively restrain cyclin E-associated genome instability.
Cancers often exhibit high levels of cyclin E expression, and aberrant cyclin E activity causes genomic instability and increased tumorigenesis. Two tumor suppressor pathways protect cells against cyclin E deregulation. The p53 pathway is induced by excess cyclin E in primary cells and opposes cyclin E activity through induction of p21Cip1. In contrast, the Fbw7 pathway targets cyclin E for degradation, and Fbw7 mutations occur commonly in cancers. We investigated the cooperativity of these two pathways in countering cyclin E-induced genomic instability in primary human cells. We find that loss of p53 and Fbw7 synergistically unmasks cyclin E-induced instability. In normal cells, impaired cyclin E degradation produces genome instability, but this is rapidly mitigated by induction of p53 and p21. In contrast, p53 loss allows the high level of cyclin E kinase activity that results from Fbw7 loss to persist and continuously drive genome instability. Moreover, p21 plays a critical role in suppressing cyclin E when Fbw7 is disabled, and in the absence of p21, sustained cyclin E activity induces rapid cell death via apoptosis. These data directly demonstrate the cooperative roles of these Fbw7 and p53 pathways in restraining cyclin E activity and its associated genome instability.
Minella
A C
AC
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Grim
J E
JE
Welcker
M
M
Clurman
B E
BE
D017209:Apoptosis; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D015162:Micronucleus Tests; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D044843:SKP Cullin F-Box Protein Ligases; D011065:Poly(ADP-ribose) Polymerases