The function of p27 KIP1 during tumor development

Abstract

Timely cell cycle regulation is conducted by sequential activation of a family of serine-threonine kinases called cycle dependent kinases (CDKs). Tight CDK regulation involves cyclin dependent kinase inhibitors (CKIs) which ensure the correct timing of CDK activation in different phases of the cell cycle. One CKI of importance is p27(KIP1). The regulation and cellular localization of p27(KIP1) can result in biologically contradicting roles when found in the nucleus or cytoplasm of both normal and tumor cells. The p27(KIP1) protein is mainly regulated by proteasomal degradation and its downregulation is often correlated with poor prognosis in several types of human cancers. The protein can also be functionally inactivated by cytoplasmic localization or by phosphorylation. The p27(KIP1) protein is an unconventional tumor suppressor because mutation of its gene is extremely rare in tumors, implying the normal function of the protein is deranged during tumor development. While the tumor suppressor function is mediated by p27(KIP1)s inhibitory interactions with the cyclin/CDK complexes, its oncogenic function is cyclin/CDK independent, and in many cases correlates with cytoplasmic localization. Here we review the basic features and novel aspects of the p27(KIP1) protein, which displays genetically separable tumor suppressing and oncogenic functions.

Figure 1

Schematic diagram of p27^KIP1 phosphorylation and binding sites. Phosphorylation sites (upper) and binding sites (lower) of full length p27^KIP1 protein are illustrated with the specific site numbers for kinases, or with the binding regions for cyclin/CDK proteins. Nuclear localization sequences (NLS) are also depicted. Note that the threonine subject to AKT phosphorylation, T157, is located within the NLS.

Figure 2

The p27^KIP1 protein is regulated by phosphorylation on multiple sites. Hypo-phosphorylated or unphosphorylated p27^KIP1 acts as a cyclin/CDK inhibitor. Multiple phosphorylated forms of the protein, through activation of various mitogenic signals, are present in cells. Phospho-p27^KIP1 diverges into discrete fates according to the location of phosphate groups. Respective functions of multifarious combinations of individual phospho sites are beyond comprehension at present. However, tyrosine phosphorylation in general renders phopho-p27^KIP1 non-inhibitory and serine/threonine phosphorylation results in cytosolic localization. Some phospho forms of the cytosolic p27^KIP1 are subject to proteasomal degradation, while others inhibit RhoA activation and facilitate cell migration.