Modeling the Budding Yeast Cell Cycle

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• Rationale
• Budding yeast biology
• Components & function
• Cell cycle progression
• Basic mechanism
• Major improvement
• Overview
• Wiring diagram
• Description
• Justification
• Cyclins
• Cdc20
• Cdh1
• Cdc14 activation
• Mitotic Exit Network
• Pds1/Esp1 interaction
• CKI
• Checkpoint proteins
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• cln1 cln2 cln3
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Cdc20

Cdc20 is essential for exit of mitosis. Deletion mutant (cdc20) arrests in M phase, with unseparated sister chromatids and high Clb2 activity (Alexandru et al., 1999; Lim et al., 1998). It is an activator of APC (for review, see (Prinz & Amon, 1999; Zachariae & Nasmyth, 1999; Morgan, 1999).

Function:

• Needed for Clb5 degradation (Irniger & Nasmyth 1997; Shirayama et al., 1999).
• Responsible for partial degradation of Clb2 at anaphase (Yeong et al., 2000; Baumer et al., 2000; Wasch & Cross, 2002).
• Initiation of anaphase by targeting Pds1 for degradation (Visintin et al., 1997, Fig. 1; Cohen-Fix et al., 1996, Fig. 7), thereby liberating Esp1 (Ciosk et al., 1998, Fig. 7).
• Degradation of Pds1 also facilitates Cdc14 release (Shirayama et al., 1999, Fig. 3; Cohen-Fix & Koshland, 1999) by activating the FEAR pathway (Pereira et al., 2002).
• Target of the spindle assembly checkpoint (for review, see Amon, 1999; Shah & Cleveland, 2000 ). Activated Mad2 (by unattached kinetochore) binds to Cdc20, and preventing the formation of APC/Cdc20 complex. Over-expression of Cdc20 can overcome the spindle assembly checkpoint evoked by nocodazole treatment and the DNA damage checkpoint evoked by shifting cdc13-1 to non-permissive temperature (Hwang et al., 1998, Fig. 2).

Level:

• Level of protein and mRNA fluctuates during the cell cycle, with pattern similar to that of Clb2 (Shirayama et al., 1998, Fig. 2; Prinz et al., 1998 , Fig. 1).
• Cdc20 transcription is activated in G2/M phase by the transcription factor complexes Mcm1/ Fkh2/Ndd1 (Spellman et al., 1998 Zhu et al., 2000; Simon et al., 2001.
• Degradation is APC-dependent (Shirayama et al., 1998, Fig. 3; Prinz et al., 1998, Fig. 5). Protein is unstable throughout the cell cycle, with a half-time of less than 3 min in S/G2/M, and is even less stable in G1 (Prinz et al., 1998, Fig. 3).

Activation/inactivation:

• In the presence of unattached kinetochores, signaling in the MAD/BUB pathway results in the inhibition of Cdc20 (for review, Gardner & Burke, 2000, Fig. 1).
• Since MAD and BUB genes are not essential genes (Li & Murray, 1991; Alexandru et al., 1999), it indicates that Cdc20 must be activated (by our hypothetical protein IE) before it can be functional.
• IE may be the phosphorylated form of the APC. Rudner & Murray (Rudner & Murray, 2000b, Fig. 2B) showed that three components of the APC core, Cdc16, Cdc23 and Cdc27 are phospho-proteins, and that they are phosphorylated by Cdc28 kinase. The non-phosphorylable APC (APC-A mutants) shows reduced binding with Cdc20, and reduced mitotic Cdc20-dependent activity. However, APC-A has normal Cdh1-dependent activity in G1.