Cdc20, short for Cell Division Cycle 20, is a protein encoded by the CDC20 gene on chromosome 1 in the human genome. It plays a regulatory role in various cellular processes, interacting with numerous other proteins throughout the cell cycle to influence how cells grow and divide.
The Role of cdc20 in Cell Division
Cdc20 functions as a substrate-specific adapter of the Anaphase-Promoting Complex/Cyclosome (APC/C), a large multi-subunit complex. The APC/C acts as an E3 ubiquitin ligase, attaching ubiquitin molecules to specific target proteins, which marks them for destruction by the proteasome. This degradation is a necessary step for the cell cycle to progress correctly. Cdc20 specifically recognizes and binds to a “destruction box” (D box) on these protein substrates.
Cdc20 functions to activate the APC/C, initiating the transition from metaphase to anaphase during cell division. During metaphase, chromosomes align at the cell’s center. The APC/C, activated by Cdc20, targets securin for degradation. Securin normally inhibits an enzyme named separase, which is responsible for cleaving cohesin proteins that hold sister chromatids together.
Once securin is degraded, separase becomes active and breaks down cohesin, allowing sister chromatids to separate and move to opposite poles of the cell. The APC/C also targets mitotic cyclins, such as cyclin B, for degradation. Degradation of cyclin B inactivates cyclin-dependent kinase 1 (CDK1), which maintains the mitotic state.
This inactivation allows the cell to exit mitosis and transition into the next cell cycle phase. The precise regulation of these events by Cdc20 and the APC/C ensures accurate chromosome segregation into daughter cells. This proper chromosome segregation is fundamental for maintaining genetic stability and preventing errors in chromosome number.
When cdc20 Goes Awry: Implications for Health
When Cdc20 does not function correctly, through overexpression or insufficient activity, it can lead to errors in cell division. This can deregulate APC/C activation, potentially causing premature anaphase progression. Such progression often results in aneuploidy, a condition where cells have an incorrect number of chromosomes.
Aneuploidy arises from chromosomal instability (CIN), which involves recurrent missegregation of chromosomes over multiple cell divisions. Overexpression of Cdc20, for example, can impair the spindle assembly checkpoint (SAC). The SAC is a cell cycle checkpoint that prevents chromosome separation until all chromosomes are properly attached to the spindle.
When Cdc20 is overexpressed, it can prematurely activate the APC/C, overriding the SAC’s control and leading to an uneven distribution of chromosomes to daughter cells. This chromosomal instability and resulting aneuploidy are frequently observed in various human diseases, most notably cancer. Many cancer cells exhibit aberrant Cdc20 levels, and its overexpression is commonly associated with tumor development and progression.
In addition to its role in aneuploidy, Cdc20 malfunction can contribute to tumor growth through other mechanisms. Studies indicate that Cdc20 can act as an oncoprotein, meaning it can promote cancer development. Its overexpression has been documented in numerous malignant tumors, including breast cancer, ovarian cancer, osteosarcoma, and hepatocellular carcinoma. This overexpression often correlates with higher tumor grades, advanced stages, and a poorer prognosis for patients.
cdc20 as a Target for Therapies
Given its significant role in regulating cell division and its association with the development and progression of various diseases, particularly cancer, Cdc20 has emerged as a promising target for therapeutic interventions. Researchers are actively exploring strategies to modulate Cdc20 activity to combat diseases where its function is dysregulated. The understanding that Cdc20 can act as an oncoprotein, promoting tumor growth when overexpressed, highlights its potential as a drug target.
The aim of these therapeutic approaches is to either inhibit Cdc20’s activity when overactive or restore its function when deficient. For instance, certain compounds are being investigated as Cdc20 inhibitors that could halt uncontrolled cell proliferation in cancer. Such inhibitors might work by preventing Cdc20 from activating the APC/C, arresting cancer cells in mitosis and leading to their demise.
Research also focuses on how Cdc20 interacts with other proteins and pathways involved in disease, providing avenues for combination therapies. For example, studies have explored combining Cdc20 inhibitors with existing chemotherapy drugs to enhance their effectiveness, particularly in cases of drug resistance. Developing therapies targeting Cdc20 aims to precisely interfere with abnormal cell division, moving towards more targeted and effective treatments.