Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo.

Publication Type:

Journal Article

Source:

Genes & development, Volume 22, Issue 12, p.1677-89 (2008)

Keywords:

2008, Animals, Basic Sciences Division, Cell Lineage, Cell Proliferation, Cells, Cultured, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Cyclin E, Epithelial Cells, Erythroid Cells, Erythropoiesis, Experimental Histopathology Core Facility, Female, Flow Cytometry Core Facility, Gene Targeting, Hematologic Diseases, Hematopoietic Stem Cells, Human Biology Division, Male, Mammary Glands, Animal, MICE, Mice, Inbred C57BL, Mice, Transgenic, PHOSPHORYLATION, PREGNANCY, Protein Kinases, Protein Processing, Post-Translational, Shared Resources

Abstract:

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.