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


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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    ABSTRACT: Histone deacetylase inhibitors (HDACIs) represent an intriguing class of pharmacologically active compounds. Currently, some HDACIs are FDA approved for cancer therapy and many others are in clinical trials, showing important clinical activities at well tolerated doses. HDACIs also interfere with the aging process and are involved in the control of inflammation and oxidative stress. In vitro , HDACIs induce different cellular responses including growth arrest, differentiation, and apoptosis. Here, we evaluated the effects of HDACIs on p27 Kip1 , a key cyclin-dependent kinase inhibitor (CKI). We observed that HDACI-dependent antiproliferative activity is associated with p27 Kip1 accumulation due to a reduced protein degradation. p27 Kip1 removal requires a preliminary ubiquitination step due to the Skp2-SCF E3 ligase complex. We demonstrated that HDACIs increase p27 Kip1 stability through downregulation of Skp2 protein levels. Skp2 decline is only partially due to a reduced Skp2 gene expression. Conversely, the protein decrease is more profound and enduring compared to the changes of Skp2 transcript. This argues for HDACIs effects on Skp2 protein posttranslational modifications and/or on its removal. In summary, we demonstrate that HDACIs increase p27 Kip1 by hampering its nuclear ubiquitination/degradation. The findings might be of relevance in the phenotypic effects of these compounds, including their anticancer and aging-modulating activities.
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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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    ABSTRACT: Podocytes are terminally differentiated cells of the glomerular filtration barrier that react with hypertrophy in the course of injury such as in membranous nephropathy (MGN). The neuronal deubiquitinase ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed and activated in podocytes of human and rodent MGN. UCH-L1 regulates the mono-ubiquitin pool and induces accumulation of poly-ubiquitinated proteins in affected podocytes. Here, we investigated the role of UCH-L1 in podocyte hypertrophy and in the homeostasis of the hypertrophy associated "model protein" p27Kip1. A better understanding of the basic mechanisms leading to podocyte hypertrophy is crucial for the development of specific therapies in MGN. In human and rat MGN, hypertrophic podocytes exhibited a simultaneous up-regulation of UCH-L1 and of cytoplasmic p27Kip1 content. Functionally, inhibition of UCH-L1 activity and knockdown or inhibition of UCH-L1 attenuated podocyte hypertrophy by decreasing the total protein content in isolated glomeruli and in cultured podocytes. In contrast, UCH-L1 levels and activity increased podocyte hypertrophy and total protein content in culture, specifically of cytoplasmic p27Kip1. UCH-L1 enhanced cytoplasmic p27Kip1 levels by nuclear export and decreased poly-ubiquitination and proteasomal degradation of p27Kip1. In parallel, UCH-L1 increased podocyte turnover, migration and cytoskeletal rearrangement, which are associated with known oncogenic functions of cytoplasmic p27Kip1 in cancer. We propose that UCH-L1 induces podocyte hypertrophy in MGN by increasing the total protein content through altered degradation and accumulation of proteins such as p27Kip1 in the cytoplasm of podocytes. Modification of both UCH-L1 activity and levels could be a new therapeutic avenue to podocyte hypertrophy in MGN.
    Full-text · Article · Jul 2014 · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
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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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