Minireview: physiological and pathological actions of RAS in the ovary.

The small G proteins of the RAS superfamily act as molecular switches in the transduction of cellular signals critical for a wide range of normal developmental events as well as pathological processes. However, the functions of Ras genes in ovarian cells have only started to be unveiled. RAS, most likely KRAS that is highly expressed in granulosa cells of growing follicles, appears crucial for mediating the gonadotropin-induced events associated with the unique physiological process of ovulation. By contrast, conditional expression of a constitutively active Kras(G12D) mutant in granulosa cells results in ovulation defects due to the complete disruption of normal follicular growth, cessation of granulosa cell proliferation, and blockage of granulosa cell apoptosis and differentiation. When the tumor suppressor Pten is disrupted conditionally in the Kras(G12D)-expressing granulosa cells, granulosa cell tumors fail to develop. However, ovarian surface epithelial cells expressing the same Pten;Kras(G12D) mutations rapidly become ovarian surface epithelial serous cystadenocarcinomas. In this minireview, we summarize some of the physiological as well as pathological functions of RAS in the rodent ovary, discuss the implications of the Kras(G12D) mutant mouse models for understanding human diseases such as premature ovarian failure and ovarian cancers, and highlight new questions raised by the results of recent studies.