PARENT SESSION
1:30 PM to 3:30 PM
Monday, April 22, 2002
Poster Session 10 Cell Cycle Effects
Room: Nevada Exhibition Center
(P15-139) p53 is involved in radiation-induced mitotic catastrophe.
Ianzini, Fiorenza*,1,2, Baman, Nicki2, Bresnahan, Lacey2, Kosmacek, Elizabeth2, Walters, Andrew2, Mackey, Michael1,2, 1 Department of Radiology, Iowa City, Iowa2 Department of Biomedical Engineering, Iowa City, Iowa
ABSTRACT-
Both chronic heat and ionizing radiation exposure induce a transient block in late S/G2 phase of the cell cycle. In some cell lines, during this delay late in the cell cycle, cyclin B1 protein accumulates to supranormal levels, cyclin B1-dependent kinase is activated, and abrogation of the G2/M checkpoint control occurs resulting in mitotic catastrophe. Using mouse embryo fibroblasts with or without mutated p53, we now show that, while both cell lines exhibit delays in late S/G2 phase post irradiation, the p53-/- MEF 10(1) cells showed elevated levels of cyclin B1 followed by mitotic catastrophe, while the wild-type MEF 12(1) cells had both a lower accumulation of cyclin B1 and lower frequencies of mitotic catastrophe. These results are also mirrored by U87-MG cells that present a wild-type p53 response post-irradiation. U87-MG cells initially in S and early G2 phases remain arrested for several days with a 4-C DNA content following 5 Gy X-irradiation, possibly due to an arrest of cells in a tetraploid G1-like state. Once cells initially in S phase progress through the DNA synthetic period, no further entry of cells into S phase is observed for up to 48 h post-irradiation and the yield of mitotic catastrophe is greatly reduced. p53 acts as a critical regulator of the cell response to DNA damage and is also involved in the transcriptional regulation of cyclin B1 in late S/G2. Thus, it is possible that in the normal cell p53 prevents the appearance of mitotic catastrophe through its specific action on cyclin B1 gene expression. Studies are currently under way to test the hypothesis that p53-dependent pathways modulate radiation-induced mitotic catastrophe. Strategies designed to augment the yield of mitotic catastrophe in tumor cells might yield improved therapeutic responses in cancer therapy. Support: CA74899; Whitaker Foundation Special Opportunity Award.
KEYWORDS: p53, cell cycle, mitotic catastrophe, radiation