Par-4 in Cell Cycle Regulation

Cell cycle must be carefully controlled to ensure genetic materials are replicated once and only once per cycle and equal sister chromatid segregation into two daughter cells. While cyclin-dependent kinases are master regulators of cell cycle, p53 and NF-κB pathways are also critical for the regulation of the cell cycle and especially the targets modulated by Par-4. Par-4 can be both cytosolic and nuclear. Cytosolic Par-4 inhibits nuclear localization of NF-κB and decreases Bcl-2 expression, leading to G1 arrest. Mechanistically, Par-4 can directly interact with NF-κB or represses ζPKC activity thus inhibits NF-κB indirectly, eventually resulting in inhibition of DROSHA expression and regulation of miRNA. Nuclear Par-4 functions as co-transcriptional factor of THAP for CCAR1, which subsequently activates the p53/p21 axis, resulting in G1 arrest. While Par-4-associated inhibition of DNA topoisomerase activity results in S phase arrest, the distribution of Par-4 in mitotic cells determines the fate of daughter cells. PLK1 is a serine/threonine kinase involved in many cell cycle-related events, including Cdk1 activation, centrosome maturation, microtubule-kinetochore attachment, bipolar spindle formation, sister chromatid segregation, and cytokinesis. PLK1 also has well-established roles in DNA damage response, especially p53 regulation, via direct phosphorylation of multiple p53 regulators such as Topors, GTSE1, and Numb. Further, PLK1 is transcriptionally regulated by NF-κB. Based on all the research performed so far, we are proposing an intriguing working model in which NF-κB, PLK1, and Par-4 are well integrated in the context of acquisition of radioresistance of prostate cancer.