User:Cellular Biochemistry II/Course 2010/Article 5



Sic1 is a protein in the budding yeast Saccharomyces cerevisiae. It is a cyclin-dependent kinase (Cdk) inhibitor ...

Function
The Anaphase-promoting complex/Cylosome (APC/c) is an ubiquitin E3-ligase complex. Once activated it attaches chains of ubiquitin molecules to a target substrate. These chains are recognised and the substrate is degraded in the proteasomes. Cdh1 is one of the co- activator proteins of APC/c and therefore contributes to the regulation of protein degradation. Cdh1 can exist in several forms. It can be phosphorylated phosphorylated by CDKs, that inactivates the co-activator and it can be dephosphorylated by Cdc14. In the dephosphorylated form it can interact with APC/c and build the active ligase APCCdh1. Suppression of Cdh1 by RNA interference leads to an aberrant accumulation of APCCdh1 target proteins, such as cyclin A and B, the kinase AuroraB, Plk1, Skp2 and Cdc20, another APC/c co- activator.

Stabilising G1-Phase
The main function of Cdh1 is to suppress the re-accumulation of mitotic cyclins and other cell cycle determinants and therefore stabilising the G1-Phase. In early mitose stage it is inactive and only becomes active in the transition from late mitosis to G1. During the cell cycle Cdk gets activated through cyclins, this leads to the mitotic entry and promotes APCCdc20 activation. APCCdc20 degrades the cyclins, this and the activation of Cdc14 leads to the creation of APCCdh1. APCCdh1 keeps the cyclin concentration low and the Cdk inactive that maintains the G1-Phase.

G1/S transition
APCCdh1 is considerate to prevent premature S-Phase entry by degrading mitotic cyclins in G1 and regulate processes unrelated to the cell cycle. To enter S-Phase APCCdh1 must be inactivated. This is made through degradation of the complex and through posphorylation of Cdh1..

Exit from Mitosis
One characteristic of the cells exit from mitosis after chromosome segregation is the removal of the mitotic determinants. This requires the inactivation of mitotic CDKs which are inactivated through ubiquitin-dependent pathways. The protein phosphatase Cdc14 dephosphorylates Cdh1 and therefore activates APCCdh1. As a result the concentration of many APCCdh1 substrates drops down and the Cell exit from mitosis..

Cdh1 functions as a tumour suppressor
Cdh1-deficient cells can proliferate but accumulate mitotic errors and have difficulties with cytokinesis. It has been shown that APCCdh1-mediated degradation of PIk1 plays an important role in preventing mitosis in cells that have DNA-damage. In healthy cells Cdh1 stays inactive from late G1 to early mitosis. It stays inactive in early mitosis and only becomes active in the transition from late mitosis to G1. A cell that suffers from DNA-damage shows an active Cdh1 already in late G1 and therefore blocks the mitotic entry. One substrate of APCCdh1 is the transcription factor Ets2, which is activated by the Ras-Raf-MAPK signalling pathway and induces the expression of cyclin D1. This pathway stimulates cell proliferation. It was shown that an increased expression of Ets2 can be associated with various cancer types, in the likes of cervical cancer or oesophageal squamous cell carcinoma.

Fuction of Cdh1 in non- dividing cells
It was shown that APCCdh1 is active in adult brain and liver tissues. It seems that the complex has a function in axongrowth, morphologie and plasticity of synapses as well as in learning and memory.

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