APC/C activator protein CDH1

APC/C activator protein CDH1 is a regulatory protein that plays a crucial role in the cell cycle by activating the Anaphase Promoting Complex/Cyclosome (APC/C), a large E3 ubiquitin ligase complex that targets cell cycle proteins for degradation, thereby controlling cell cycle progression and ensuring proper cell division. CDH1 is particularly important for the transition from mitosis to the G1 phase of the cell cycle.

Function

The primary function of CDH1 is to activate the APC/C during the late mitotic and G1 phases of the cell cycle. By doing so, it facilitates the ubiquitination and subsequent degradation of key cell cycle regulators, including securin and cyclin B, which are necessary for the separation of sister chromatids and exit from mitosis, respectively. This degradation process is essential for ensuring that cells do not enter the next phase of the cell cycle with damaged or incomplete DNA, thereby maintaining genomic stability.

CDH1 also plays a role in controlling the G1/S transition by targeting for degradation specific S-phase promoting factors and cyclin-dependent kinase (CDK) inhibitors, which are involved in DNA replication and repair. This ensures that cells only proceed to S-phase when they are fully prepared, further safeguarding genomic integrity.

Regulation

The activity of CDH1 is tightly regulated by several mechanisms, including phosphorylation and dephosphorylation. During mitosis, CDH1 is phosphorylated by Cdk1, which inhibits its interaction with the APC/C, thus preventing premature activation of the APC/C. As cells exit mitosis, CDH1 is dephosphorylated, which allows it to bind to and activate the APC/C, leading to the degradation of mitotic cyclins and other substrates.

Additionally, the protein levels and activity of CDH1 are regulated by its own ubiquitination and degradation, which is mediated by the APC/C in conjunction with other E3 ubiquitin ligases. This creates a feedback loop that ensures the precise timing of CDH1 activity and, by extension, cell cycle progression.

Clinical Significance

Alterations in CDH1 function have been implicated in the development of various cancers. Overexpression or hyperactivation of CDH1 can lead to premature degradation of cell cycle regulators, resulting in cell cycle arrest, senescence, or apoptosis, which can act as a tumor suppressor mechanism. Conversely, loss of CDH1 function can contribute to uncontrolled cell proliferation, genomic instability, and tumor progression, highlighting its potential as a therapeutic target in cancer treatment.

See Also

• Cell cycle
• Ubiquitin-proteasome system
• Oncogene
• Tumor suppressor gene