Transient overexpression of the mitotic checkpoint gene Mad2 leads to chromosome instability and tumors in mice Free

SY01-02

Mad2 is an essential component of the spindle checkpoint that blocks activation of separase and dissolution of sister chromatids until microtubule attachment to kinetochores is complete. Mad2 is also an E2F target gene whose expression is deregulated by loss of the tumor supressor protein Rb. We present evidence that overexpression of Mad2 in transgenic mice leads to a wide variety of neoplasias, appearance of broken chromosomes, anaphase bridges and whole chromosome gains and losses, as well as acceleration of myc-induced lymphomagenesis. Moreover, continued overexpression of Mad2 is not required for tumor maintenance unlike the majority of oncogenes studied to date. These results demonstrate that transient Mad2 overexpression and chromosome instability can be an important stimulus in the initiation and progression of different cancer subtypes. In addition, these studies suggest that Mad2 may be a key effector of tumorigenesis initiated by loss of the Rb tumor supressor.