Cdc23 Activators

Cdc23, as a crucial component of the anaphase-promoting complex/cyclosome (APC/C), plays a pivotal role in regulating cell cycle progression, particularly in facilitating the transition from metaphase to anaphase by targeting specific cell cycle proteins for ubiquitination and proteasomal degradation. The chemical activators identified for Cdc23 indirectly enhance its functional activity by modulating the cellular demand for APC/C activity. For instance, MG132, a proteasome inhibitor, increases the cellular concentration of ubiquitinated proteins, which may lead to a compensatory upregulation of APC/C activity to maintain protein homeostasis, indirectly enhancing the functional role of Cdc23. Similarly, CDK inhibitors like Apigenin, Roscovitine, and Purvalanol A induce cell cycle arrest, thereby potentially increasing the necessity for APC/C-mediated proteolysis to facilitate cell cycle progression, indirectly promoting the function of Cdc23.

The indirect enhancement of Cdc23's activity is also supported by chemicals that affect mitotic progression. Nocodazole and Taxol, which disrupt microtubule dynamics, lead to cell cycle arrest at the G2/M phase, suggesting a subsequent increase in APC/C activity to overcome the arrest, thereby indirectly enhancing therole of Cdc23 in the process. Inhibitors of kinases involved in cell cycle regulation, such as Tofacitinib, which targets JAK signaling, and Alisertib and ZM447439, which inhibit Aurora kinases, lead to alterations in cell cycle checkpoints, indirectly necessitating an increase in APC/C activity and highlighting the importance of Cdc23 in these regulatory mechanisms. Moreover, Trichostatin A, by causing histone deacetylation and G2/M arrest, and Thapsigargin, by dysregulating calcium signaling, create cellular conditions that can indirectly elevate the activity of the APC/C complex. The modulation of cell cycle arrest and mitotic progression by these chemicals underscores the essential role of Cdc23 in maintaining proper cell cycle control, as their actions converge on pathways that ultimately enhance the activity of this critical regulatory protein.