Cynthia Irvin Behe, M.S.

Thesis research performed under the guidence of Dr. William K. Kaufmann

ABSTRACT
    To examine the role of cell cycle checkpoint function in rat hepatocarcinogenesis, we analyzed G1, G2, and mitotic spindle assembly checkpoint responses in normal rat hepatocytes, hepatic epithelial stem-like cells (WB-F344), and transformed derivatives.  These analyses tested the hypothesis that loss of cell cycle checkpoint function provides a growth advantage by allowing cell division under inappropriate conditions as well as inducing genetic instability.  Primary hepatocytes and WB-F344 cells had a functional G1 checkpoint.  Defective G1 checkpoint function was seen in 4 of 8 transformed lines sometimes associated with alterations in p53 as well as aberrant mitotic spindle assembly checkpoint.  Primary hepatocytes expressed a radiation-induced G2 delay while all transformed hepatic cell lines displayed G2 checkpoint attenuation.  Moreover, WB-F344 cells also displayed significant age-related attenuation of G2 checkpoint function.  Abnormalities in cell cycle checkpoint function therefore were detected in transformed hepatocytes and WB-F344 cells at stages of hepatocarcinogenesis preceding tumorigenicity.