p27(Kip1): Regulation and function of a haploinsufficient tumor suppressorand its misregulation in cancer

A major function of p27, also known as Kipl, is to bind and inhibit cyclin/ cyclin-dependent kinase complexes, thereby blocking cell cycle progression. As p27 operates at the heart of the cell cycle, it is perhaps not surprisi ng that it is emerging as a key player in multiple cell fate decisions incl uding proliferation, differentiation, and cell death. The central role of p 27 makes it important in a variety of disease processes that involve aberra tions in cellular proliferation and other cell fates. Most notable among th ese processes is neoplasia. A large number of studies have reported that p2 7 expression is frequently downregulated in human tumors. In most tumor typ es, reduced p27 expression correlates with poor prognosis, making p27 a nov el and powerful prognostic marker. In addition to these practical implicati ons, murine and tissue culture models have shown that p27 is a potent tumor suppressor gene for multiple epithelially derived neoplasias. Loss of p27 cooperates with mutations in several oncogenes and tumor suppressor genes t o facilitate tumor growth, indicating that p27 may be a "nodal point" for t umor suppression, In contrast to most tumor suppressor genes studied to dat e, which are recessive at the cellular level, p27 is haploinsufficient for tumor suppression. The fact that tumor suppression by p27 is critically dep endent on the absolute level of p27 expression indicates that p27 acts as a rheostat rather than as an on/off switch to control growth and neoplasia. (C) 2001 Academic Press.