Exit from mitosis is regulated by Drosophila fizzy and the sequential destruction of cyclins A, B and B3.

Abstract

While entry into mitosis is triggered by activation of cdc2 kinase, exit from mitosis requires inactivation of this kinase. Inactivation results from proteolytic degradation of the regulatory cyclin subunits during mitosis. At least three different cyclin types, cyclins A, B and B3, associate with cdc2 kinase in higher eukaryotes and are sequentially degraded in mitosis. We show here that mutations in the Drosophila gene fizzy (fzy) block the mitotic degradation of these cyclins.Moreover, expression of mutant cyclins (Acyclins) lacking the destruction box motif required for mitotic degradation affects mitotic progression at distinct stages. Acyclin A results in a delay in metaphase, Acyclin B in an early anaphase arrest and Acyclin B3 in a late anaphase arrest, suggesting that mitotic progression beyond metaphase is ordered by the sequential degradation of these different cycfins. Coexpression of Acyclins A, B and B3 allows a delayed separation of sister chromosomes, but interferes with chromosome segregation to the poles. Mutations infzy block both sister chromosome separation and segregation, indicating that fzy plays a crucial role in the metaphase/anaphase transition.

An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63

“…The order of APC directed substrate degradation is illustrated in figure 1.4. Firstly, APC/Cdc20 targets Cyclin A in prometaphase, Cyclin A destruction is thought to be a required step in the onset of anaphase (Geley et al, 2001;Sigrist et al, 1995;den Elzen and Pines, 2001). …”

The anaphase-promoting complex: a key factor in the regulation of cell cycle

“…However, the first direct connection between this protein and APC-dependent degradation of the mitotic cyclins was described in Drosophila in which a mutation in the gene encoding the Cdc20 ortholog, Fizzy, blocked mitotic degradation of cyclin A, B and B3 (Sigrist et al, 1995). A subsequent study in this species described the presence of a new protein with significant homology to Fizzy that was named Fizzy-Related, and that corresponds to the Drosophila Cdh1/Hct1 ortholog.…”

ΔMEKK3:ER* activation induces a p38α/β2-dependent cell cycle arrest at the G2 checkpoint

“…The ubiquitin ligase subunits, Cdc20 and Cdh1, are postulated to direct cyclins A and B respectively for ubiquitination, thereby flagging them for degradation by the proteasome (Dawson et al, 1995;Sigrist et al, 1995;Sudakin et al, 1995;Kotani et al, 1999). Whilst preliminary analysis has failed to show an increase in association between the proteasome subunit Cdc27 and Cdh1 upon activation of DMEKK3:ER* stimulation (data not shown), we cannot rule out the possibility that DMEKK3:ER* is subtly controlling the activity of this complex, or that other ubiquitin ligases are involved.…”