Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo.
Phosphorylations within N- and C-terminal degrons independently control the binding of cyclin E to the SCF(Fbw7) and thus its ubiquitination and proteasomal degradation. We have now determined the physiologic significance of cyclin E degradation by this pathway. We describe the construction of a knockin mouse in which both degrons were mutated by threonine to alanine substitutions (cyclin E(T74A T393A)) and report that ablation of both degrons abolished regulation of cyclin E by Fbw7. The cyclin E(T74A T393A) mutation disrupted cyclin E periodicity and caused cyclin E to continuously accumulate as cells reentered the cell cycle from quiescence. In vivo, the cyclin E(T74A T393A) mutation greatly increased cyclin E activity and caused proliferative anomalies. Cyclin E(T74A T393A) mice exhibited abnormal erythropoiesis characterized by a large expansion of abnormally proliferating progenitors, impaired differentiation, dysplasia, and anemia. This syndrome recapitulates many features of early stage human refractory anemia/myelodysplastic syndrome, including ineffective erythropoiesis. Epithelial cells also proliferated abnormally in cyclin E knockin mice, and the cyclin E(T74A T393A) mutation delayed mammary gland involution, implicating cyclin E degradation in this anti-mitogenic response. Hyperproliferative mammary epithelia contained increased apoptotic cells, suggesting that apoptosis contributes to tissue homeostasis in the setting of cyclin E deregulation. Overall these data show the critical role of both degrons in regulating cyclin E activity and reveal that complete loss of Fbw7-mediated cyclin E degradation causes spontaneous and cell type-specific proliferative anomalies.
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Alex C
AC
Minella
Keith R
KR
Loeb
Andrea
A
Knecht
Markus
M
Welcker
Barbara J
BJ
Varnum-Finney
Irwin D
ID
Bernstein
James M
JM
Roberts
Bruce E
BE
Clurman
D000818:Animals; D019070:Cell Lineage / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D041905:Erythroid Cells / Q000473:pathology; D004920:Erythropoiesis / Q000235:genetics; D005260:Female; D018390:Gene Targeting; D006402:Hematologic Diseases / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011247:Pregnancy; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology
D019927:Cyclin E; D011494:Protein Kinases