The Interactive Fly
Evolutionarily conserved developmental pathways
Cell cycle 4: Mitotic progression and exit from mitosis - a conserved function for Fizzy and Fizzy-related
The anaphase-promoting complex/cyclosome (APC) is a multisubunit ubiquitin ligase that targets several mitotic regulators for degradation and thereby triggers an exit from mitosis. APC activity is restricted to mitotic stages M and G1. This restriction is achieved by the cell cycle-dependent association of proteins encoded by fizzy and fizzy-related genes functioning during M and G1 respectively. fzr bears the accepted FlyBase designation of retina aberrant in pattern, because of a study showing that mutants show a disruption in eye patterning (Karpilow, 1989). Nevertheless, the alternative name fizzy-related is widely used. fzr, a conserved eukaryotic gene, negatively regulates the levels of cyclins A, B, and B3. These mitotic cyclins that bind and activate cdk1(cdc2) are rapidly degraded during exit from M and during G1. fzr is required for cyclin removal during G1 when the embryonic epidermal cell proliferation stops and during G2 during the cell cycle preceding salivary gland endoreduplication. Loss of fzr causes progression through an extra division cycle in the epidermis and inhibition of endoreduplication in the salivary gland, in addition to failure of cyclin removal. Conversely, premature fzr overexpression down-regulates mitotic cyclins, inhibits mitosis, and transforms mitotic cycles into endoreduplication cycles (Sigrist, 1997).
Binding of Cdc20 (the homolog of Fizzy in yeast and vertebrates) and Cdh1 (the homolog of Fizzy-related in yeast and vertebrates) to the APC is differentially regulated. APC-Cdc20 activity is present during mitosis and initiates the metaphase-anaphase transition. The association of Cdc20 with the APC requires phosphorylation of at least one subunit of the APC. Several mitotic kinases have been implicated in this phosphorylation. The dependency of APC phosphorylation on Cdc20 binding ensures that APC-Cdc20 is only active during mitosis. During prophase and prometaphase, APC-Cdc20 activity is furthermore restrained by the spindle checkpoint. This system monitors the presence of unattached kinetochores. Until kinetochores are bound by spindles, they serve as an assembly point for active Mad2 protein. Mad2 binds to Cdc20 and inhibits APC activity. Once all kinetochores are attached and chromosomes are aligned on the metaphase plate, Mad2 inhibition of APC-Cdc20 activity is released (Grosskortenhaus, 2002 and references therein).
Cdh1 is found in association with the APC during later stages of mitosis and G1. This interaction depends on the phosphorylation status of Cdh1 (Kramer, 2000; Zachariae, 1998). Only unphosphorylated Cdh1 is able to bind to and activate the APC (Kotani, 1999; Kramer, 2000). Cdk1 and Cdk2 mediate Cdh1 phosphorylation. Thus, only during stages of low Cdk kinase activity will Cdh1 activate the APC. These requirements are fulfilled during later stages of mitosis, when APC-Cdc20 has induced the degradation of mitotic cyclins, and during G1, when Cdk kinase activity is low. However, the G2 stage is also characterized by low Cdk kinase activity. How Cdh1-dependent APC activity is prevented in these situations has not been addressed so far (Grosskortenhaus, 2002 and references therein).
The mitotic cyclins in Drosophila (Cyclin A [CycA], Cyclin B [CycB], and Cyclin B3) are stable in interphase, degraded during mitosis, and continue to be unstable throughout G1. Cdc20Fzy is required for mitotic cyclin destruction at the metaphase-anaphase transition and is thought to mediate the bulk of cyclin degradation in the first 16 cell cycles in Drosophila. Mutants in fzy arrest in metaphase of cell cycle 16 when the maternal supply of Cdc20Fzy is exhausted. Overexpression of fzy does not cause abnormal cyclin destruction. Thus, Cdc20Fzy is not able to activate the APC at other cell cycle stages. This likely reflects the inability of Cdc20 to interact with unphosphorylated APC (Grosskortenhaus, 2002 and references therein).
Analysis in Drosophila demonstrates that fzr is expressed and of crucial importance when cells terminate cell proliferation during embryogenesis. Loss of fzr results in progression through an extra cell cycle in epidermal cells and in inhibition of endoreduplication in salivary glands. These deviations from the normal developmental cell cycle program are accompanied by a failure to down-regulate mitotic cyclins (cyclins A, B, and B3) that bind and activate cdk1(cdc2) kinase. Premature fzr overexpression, when epidermal cells still proliferate, down-regulates mitotic cyclins followed by inhibition of mitosis. All of these findings are consistent with the idea that Fzr activates degradation of mitotic cyclins and thereby prevents ectopic cdk1(cdc2) activity when cells become postmitotic (Sigrist, 1997).
date revised: 5 May 2005
Developmental Pathways conserved in Evolution
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