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Key words: CKI, cell-cycle inhibitors, p21Cip1, p27Kip1, p57Kip2
Summary
The cell cycle is a precisely controlled cellular program that ensures normal cellular proliferation and development. The cyclin-dependant kinases (CDK) are molecules central to the continued progression through the cell-cycle checkpoints and as such are regulated by various mechanisms including cyclin levels, phosphorylation/dephosphorylation and cyclin-dependant kinase inhibitors (CKI). The CKIs are grouped into two families based on their structure and function, four Ink4 CKIs and three Cip/Kip CKIs. Abnormalities in these proteins can give rise to developmental defects and cancer. In this review, we will discuss the biochemistry and cell biology of the each of the Cip/Kip CKIs, their role in development as evidenced by targeted mutations in mice, and their role as possible tumor suppressor genes.
Introduction
The cell cycle is a well-controlled cellular machine that is involved in the growth, division, differentiation, and death of cells. The cyclin-dependant kinases (CDKs) are central to progression through the cell cycle, in particular the G1-S phase checkpoint. Generally speaking, transiently expressed proteins (the cyclins) are up-regulated by various mitogens, activating the CDKs that in turn phosphorylate various substrates allowing for DNA synthesis, mitogenesis and cytokinesis in a highly regulated fashion. The function of CDKs are controlled in several ways, such as binding to cyclins (positive regulation), phosphorylation and dephosphorylation, and binding to CDK inhibitors (CKIs) (reviewed in [1,2]) (Figure 1).
The CKI proteins have been divided into 2 classes based on their primary amino-acid structure and by the targets in the cell cycle at which they act. The first family, the INK4 (Inhibitors of CDK4) proteins are composed of 4 gene products and selectively inhibit CDK4 and CDK6. The four INK4 inhibitors (p16INK4a, p15INK4b, p18INK4c, and p19INK4d) do not bind to any of the other CDKs or to the cyclins. In contrast, the Cip/Kip inhibitors (CDK interacting protein/Kinase inhibitory protein) constitute three proteins p21Cip1, p27Kip1, and p57Kip2. These CKIs inhibit a wider range of CDKs. Unlike the INK4a family, the Cip/Kip proteins bind to both the cyclin and the cyclin-dependant kinase that is important for their function as both a positive and negative regulator of G1-phase progression (reviewed in [2-4]).
The various Cip/Kip proteins are regulated differently through external and internal factors, have different tissue expression,...