Article

p27Kip1 Metabolism: A Fascinating Labyrinth

Department of Biochemistry and Biophysics F. Cedrangolo, Second University of Naples, Naples, Italy.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 05/2007; 6(9):1053-61. DOI: 10.4161/cc.6.9.4142
Source: PubMed

ABSTRACT

The progression through the phases of cell division cycle is regulated by different cyclins and cyclin-dependent kinases (CDKs) complexes. Due to their key function, the activity of cyclin/CDK complexes is controlled by several mechanisms, including the inhibition by a number of proteins collectively defined CDK inhibitors or CKIs. Among the CKIs, p27Kip1 represents a protein of central activity for the control of several phenotypes, including proliferation, differentiation and malignant transformation. p27Kip1 belongs to the growing family of "natively unfolded," "intrinsically disordered" or "intrinsically unstructured" proteins. The disorder proteins present a very large number of possible conformations that, after the binding, converge to a well-defined structure with an extraordinary affinity for the target. As matter of fact, the absence of a pre-existing folding strongly facilitates p27Kip1 interaction with a number of targets. Until recently, p27Kip1 has been solely viewed as a nuclear protein with the function of modulating cyclin-CDK activity and hence, cell cycle progression. However, exhaustive studies have now demonstrated that the protein plays additional roles outside of the nucleus, including, particularly, the control of cell motility. Thus, the cellular localization is of fundamental importance in p27Kip1 function. Accordingly, at least two different mechanisms of degradation, occurring either in the nucleus or in the cytosol, have been observed. Convincing evidences have demonstrated that p27Kip1 is a phosphoprotein showing at least six to eight phosphorylatable residues. However, the precise functional roles of the phosphorylations and the identification of the kinases responsible for the post-synthetic modifications are still debated. In this brief review, we will report the Literature data that connect the post-synthetic modifications of p27Kip1 with its function, localization and metabolism. The picture that emerges demonstrates that several of the pieces of the CKI metabolism are still nebulous.

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Available from: Adriana Oliva, Apr 17, 2014
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    • "The protein also modulates, in mid-G1, the assembly and nuclear import of cyclin Ds-CDK4/6 complexes. p27 Kip1 cellular content is regulated by intricate posttranslational mechanisms and by proteasome removal ([20,21]and references therein). p27 Kip1 degradation is controlled by at least two distinct ubiquitination processes which occur separately in the nuclear and in the cytosolic compartments. "
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    • "In all systems that were evaluated, transcriptional levels of p27 Kip1 were not changed, indicating post-translational mechanisms of p27 Kip1 regulation through UCH-L1. P27 Kip1 belongs to the family of " intrinsically unstructured " [35] proteins and therefore presents a large number of possible confirmations and interactions with a multitude of targets. It was demonstrated in lung tumor cells that UCH-L1 could form hetero-trimeric complexes through association with JAB-1, a multifunction protein, and p27 Kip1 [28]. "
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    • "Cyclin D1 is a major mitogen-induced regulator of cell cycle progression that has a central function in regulating G1 progression and forms a complex with and functions as a regulatory subunit of CDK4 or CDK6 [26]. Cyclin E/CDK2 complexes have a pivotal role in G1 to S phase transition [27]. Cyclin A2 binds and activates CDC2 or CDK2 kinases and thus promotes both cell cycle G1/S and G2/M transitions. "
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