| First Author | Minella AC | Year | 2008 |
| Journal | Genes Dev | Volume | 22 |
| Issue | 12 | Pages | 1677-89 |
| PubMed ID | 18559482 | Mgi Jnum | J:136692 |
| Mgi Id | MGI:3796791 | Doi | 10.1101/gad.1650208 |
| Citation | Minella AC, et al. (2008) Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes Dev 22(12):1677-89 |
| abstractText | 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. |
