Phosphorylation-Dependent Ubiquitination of Cyclin E by the SCF ^Fbw7 Ubiquitin Ligase

Abstract

Cyclin E binds and activates the cyclin-dependent kinase Cdk2 and catalyzes the transition from the G1 phase to the S phase of the cell cycle. The amount of cyclin E protein present in the cell is tightly controlled by ubiquitin-mediated proteolysis. Here we identify the ubiquitin ligase responsible for cyclin E ubiquitination as SCFFbw7 and demonstrate that it is functionally conserved in yeast, flies, and mammals. Fbw7 associates specifically with phosphorylated cyclin E, and SCFFbw7 catalyzes cyclin E ubiquitination in vitro. Depletion of Fbw7 leads to accumulation and stabilization of cyclin E in vivo in human and Drosophila melanogaster cells. Multiple F-box proteins contribute to cyclin E stability in yeast, suggesting an overlap in SCF E3 ligase specificity that allows combinatorial control of cyclin E degradation.

Upregulation of miR-27a contributes to the malignant transformation of human bronchial epithelial cells induced by SV40 small T antigen

“…Meanwhile, Fbxw7 expression has been found to be suppressed in a number of tumors (Rhodes et al, 2007). Indeed, Fbxw7 is an evolutionarily conserved E3 ubiquitin ligase that is thought to be involved in regulating cell growth and apoptosis by ubiquitination of cyclin E (Koepp et al, 2001), Notch 1 , c-Myc (Welcker et al, 2004), c-Jun (Wei et al, 2005) and other downstream target genes. Mutation of a single Fbxw7 allele was found to cooperate with p53 in tumor development, suggesting that it is a haploinsufficient tumor suppressor (Mao et al, 2004).…”

The Emerging Role of the COP9 Signalosome in Cancer

“…[10][11][12]. This function has been proposed to be mediated by the catalytic subunit CSN5 but requires the assembly of the entire CSN holocomplex (10)(11)(12)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). The deneddylation of Cullins is required for Cullin-mediated degradation of E3 substrates.…”

Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1

“…7 Ultimately, deregulation of cyclin E1 results in disrupted DNA replication, centrosomal aberrations, chromosome instability and an increased incidence of chromosome breaks and translocations. 5,[8][9][10] Deletion or mutation of the F-box protein Fbw7, part of the Skp1-Cul1-Rbx1 ubiquitin ligase complex (SCF Fbw7 ) that targets cyclin E for proteosomal degradation, 11,12 is also highly correlated with chromosome instability. 13 Although cyclins E1 and E2 are often coordinately regulated, share strong sequence similarity in functional important regions, including the cyclin box and centrosomal localization sequence, 14 and appear to be functionally redundant during murine development, 1,[15][16][17][18][19] there is accumulating evidence that, like many cyclins, they have distinct roles under some circumstances.…”