Circadian variation in the expression of cell-cycle proteins in human oralepithelium

At the tissue level, there is experimental and clinical data to suggest a c ytokinetic coordination of the cell cycle with a greater proportion of cycl ing cells entering S-phase and mitosis at specific times of the day. The as sociation of certain cell-cycle proteins with defined events in the cell cy cle is well established and may be used to study the timing of cell-cycle p hases over 24 hours. In this study oral mucosal biopsies were obtained from six normal human volunteers at 4-hour intervals, six times over 24 hours. Using immunohistochemistry, the number of positive cells expressing the pro teins p53, cyclin-E, cyclin-A, cyclin B1, and Ki-67 was determined for each biopsy and expressed as the number of positive cells per mm of basement me mbrane. We found a statistically significant circadian variation in the nuc lear expression of all of these proteins with the high point of expression for p53 at 10:56 hours, cyclin-E at 14:59 hours, cyclin-A at 16:09 hours, c yclin-B1 at 21:13 hours, and Ki-67 at 02:50 hours. The circadian variation in the nuclear expression of cyclins-E (G1/S phase), -A (G2-phase), and -B1 (M-phase) with a normal physiological progression over time suggests a sta tistically significant circadian variation in oral epithelial cell prolifer ation. The finding of a circadian variation in the nuclear expression of p5 3 protein corresponding to late G1 is novel. This information has clinical implications regarding the timing of chemotherapy and radiotherapy.