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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    • "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.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 07/2014; 1842(7). DOI:10.1016/j.bbadis.2014.02.011 · 4.88 Impact Factor
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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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    ABSTRACT: Background. Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies worldwide. It is characterized by its high invasive and metastatic potential. Leprecan-like 1 (LEPREL1) has been demonstrated to be downregulated in the HCC tissues in previous proteomics studies. The present study is aimed at a new understanding of LEPREL1 function in HCC. Methods. Quantitative RT-PCR, immunohistochemical analysis, and western blot analysis were used to evaluate the expression of LEPREL1 between the paired HCC tumor and nontumorous tissues. The biology function of LEPREL1 was investigated by Cell Counting Kit-8 (CCK8) assay and colony formation assay in HepG2 and Bel-7402 cells. Results. The levels of LEPREL1 mRNA and protein were significantly lower in the HCC tissues as compared to those of the nontumorous tissues. Reduced LEPREL1 expression was not associated with conventional clinical parameters of HCC. Overexpression of LEPREL1 in HepG2 and Bel-7402 cells inhibited cell proliferation (P < 0.01) and colony formation (P < 0.05). LEPREL1 suppressed tumor cell proliferation through regulation of the cell cycle by downregulation of cyclins. Conclusions. Clinical parameters analysis suggested that LEPREL1 was an independent factor in the development of HCC. The biology function experiments showed that LEPREL1 might serve as a potential tumor suppressor gene by inhibiting the HCC cell proliferation.
    Gastroenterology Research and Practice 11/2013; 2013:109759. DOI:10.1155/2013/109759 · 1.75 Impact Factor
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    • "p27Kip1 is a member of the Cip/Kip subfamily of cyclin-dependent kinase inhibitors (CKIs) and exerts its most well-known function as a cell cycle inhibitor. It belongs to the so-called 'natively unfolded proteins' (Borriello et al., 2007). The 'intrinsic disorder' and flexibility of p27Kip1 are evolutionarily advantageous and enable p27Kip1 to participate in diverse cellular activities, including regulation of cell division, transcription and translation, signal transduction, protein phosphorylation , and transport and regulation of assembly or disassembly of multi-protein complexes (Galea et al., 2008). "
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    ABSTRACT: STUDY QUESTION: Why are female mice that lack a functional p27 protein infertile?SUMMARY ANSWERThe absence of a functional p27 leads to a dramatic increase in the number of multi-oocyte follicles (MOFs) in juvenile female mice; p27 would promote the individualization of follicles favoring the development of fertile eggs.WHAT IS KNOWN ALREADYp27-/- female mice are infertile. p27 suppresses excessive follicular endowment and activation and promotes follicular atresia in mice.MATERIALS AND METHODS Ovaries from wild type (WT) and p27Kip1 mutant mice aged 2, 4 and 12 weeks were subjected to immunohistochemistry/ immunofluorescence. The slides with whole organs serially sectioned were scanned and examined by image analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with WT, p27Kip1 mutant pre-pubertal mice had a greater number of oocytes, a greater number of growing follicles and a greater number of MOFs. These differences were statistically significant (P < 0.05), particularly in the case of MOFs (P > 0.001). The unusually large number of MOFs in juvenile p27-deficient mice is a novel observation. In WT mice p27 protein remains present in the oocyte nucleus but gradually decreases in the ooplasm during follicular growth, while granulosa cells show dynamic, follicle stage-related changes. LIMITATIONS, REASONS FOR CAUTION: These results have been obtained in mice and they cannot be directly extrapolated to humans. WIDER IMPLICATIONS OF THE FINDINGS: The dramatic increase in the numbers of MOFs in juvenile p27 mutants has not been previously reported. The number of MOFs declines sharply as the mice become sexually mature, pointing to their negative selection. These findings open a new approach to the study of sterility.STUDY FUNDING/COMPETING INTERESTSThis study has been funded by the Basque Government, Dept. of Health grant 2007111063 and Dept. of Industry (Saiotek) grant S-PC11UN008. Jairo Perez-Sanz was the recipient of a grant from Fundación Jesús de Gangoiti Barrera. The authors have no conflicts of interest to declare.
    Human Reproduction 01/2013; 28(4). DOI:10.1093/humrep/des436 · 4.57 Impact Factor
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