A mouse model for cyclin E-dependent genetic instability and tumorigenesis.
Ubiquitination of murine cyclin E is triggered by phosphorylation on threonine 393. Cyclin E(T393A) knockin mice exhibited increased cyclin E stability, but no phenotypic abnormalities. Importantly, loss of the p53 pathway exacerbated the effect of the T393A mutation. Thus, in p21(-/-) cells the T393A mutation had an exaggerated effect on cyclin E abundance and its associated kinase activity, which caused abnormal cell cycle progression, and genetic instability involving chromosome breaks and translocations. Moreover, cyclin E(T393A) acted synergistically with p53 deficiency to accelerate tumorigenesis in cyclin E(T393A) p53(-/-) mice; Ras more readily transformed cyclin E(T393A) p53(-/-) cells than p53(-/-) cells in vitro; and cyclin E(T393A) mice had a greatly increased susceptibility to Ras-induced lung cancer.
Loeb
Keith R
KR
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98029, USA.
Kostner
Heather
H
Firpo
Eduardo
E
Norwood
Thomas
T
D Tsuchiya
Karen
K
Clurman
Bruce E
BE
Roberts
James M
JM
D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D019457:Chromosome Breakage; D019927:Cyclin E / Q000235:genetics / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020732:Cytogenetic Analysis; D004195:Disease Models, Animal; D005260:Female; D042822:Genomic Instability; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D013912:Threonine / Q000737:chemistry / Q000235:genetics; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D013912:Threonine; D018631:ras Proteins