CDK Inhibitors : Cell Cycle regulators and Beyond

Université de Toulouse - LBCMCP and CNRS - UMR5088, Toulouse, France.
Developmental Cell (Impact Factor: 9.71). 03/2008; 14(2):159-69. DOI: 10.1016/j.devcel.2008.01.013
Source: PubMed


First identified as cell cycle inhibitors mediating the growth inhibitory cues of upstream signaling pathways, the cyclin-CDK inhibitors of the Cip/Kip family p21Cip1, p27Kip1, and p57Kip2 have emerged as multifaceted proteins with functions beyond cell cycle regulation. In addition to regulating the cell cycle, Cip/Kip proteins play important roles in apoptosis, transcriptional regulation, cell fate determination, cell migration and cytoskeletal dynamics. A complex phosphorylation network modulates Cip/Kip protein functions by altering their subcellular localization, protein-protein interactions, and stability. These functions are essential for the maintenance of normal cell and tissue homeostasis, in processes ranging from embryonic development to tumor suppression.

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Available from: James M Roberts, Dec 17, 2013
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    • "Cyclin-dependent kinase (CDK) inhibitors (CKIs) act on various cyclin-CDK complexes during different phases of the cell cycle. Particularly, CKIs, such as p21 Cip1 , p27 Kip1 , and p57 Kip2 , have been shown to mediate the G1 arrest in response to an array of stimuli including DNA damage, mitogen deprivation, or drug treatments [19] [20] [21]. Here, we report a study on the effect of HDACIs on p27 Kip1 , a tight-binding inhibitor of CDK complexes, belonging to the Cip/Kip family. "
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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.
    Full-text · Article · Jan 2016 · Oxidative medicine and cellular longevity
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    • "In addition, CDK activity is also regulated through their interaction with inhibitory proteins, such as p21 (also known as CDKN1A) and p27 (also known as CDKN1B). These proteins interact directly with the CDKs and inhibit the interaction with their regulatory cyclin (Besson et al., 2008). "
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    ABSTRACT: PHD1 belongs to a family of prolyl hydroxylases (PHDs), which are involved in the control of the cellular response to hypoxia. PHD1 is also able to regulate mitotic progression through the regulation of a critical centrosomal protein Cep192, establishing a link between oxygen sensing and the cell cycle machinery. Here, we demonstrate that PHD1 is phosphorylated by CDK2, 4 and 6 at Serine 130. This phosphorylation fluctuates with the cell cycle and can be induced through oncogenic activation. Functionally, PHD1 phosphorylation leads to increased induction of HIF protein levels and activity during hypoxia. PHD1 phosphorylation does not alter its intrinsic enzymatic activity, but instead decreases the interaction between PHD1 and HIF1α. Interestingly, while phosphorylation of PHD1 at Serine 130 lowers its activity towards HIF1α, this modification increases PHD1's activity towards Cep192. These results establish a mechanism by which cell cycle mediators, such as CDKs, temporally control the activity of PHD1, directly altering the regulation of HIF1α and Cep192.
    Full-text · Article · Dec 2015 · Journal of Cell Science
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    • "An important group of CDKI is the KIP/CIP family consisting of p21, p27 and p57. While these proteins share a similar N terminal structure, the remainder of their structure is sufficiently different that each may serve different functions [42]. Moreover, different mechanisms may control these CDKIs at different stages of the cell cycle. "
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    ABSTRACT: Disorders of vascular function contribute importantly to cardiovascular disease which represents a substantial cause of morbidity and mortality worldwide. An emerging paradigm in the study of cardiovascular diseases is that protein ubiquitination and turnover represent key pathological mechanisms. Our understanding of these processes in the vasculature is growing but remains incomplete. Since protein ubiquitination and turnover can represent a terminal event in the life of a given protein, entry into these pathways must be highly regulated. However, at present understanding of these regulatory mechanisms, particularly in the vasculature, is fragmentary. The COP9 (constitutive photomorphogenic mutant 9) signalosome (CSN) is a heteromeric protein complex implicated in the control of protein degradation. The CSN participates critically in the control of Cullin Ring Ligases (CRLs), at least in part via the detachment of a small protein, Nedd8 (deneddylation). CRLs are one of the largest groups of ubiquitin ligases, which represent the most selective control point for protein ubiquitination. Thus, the CSN by virtue of its ability to control the CRLs ubiquitin ligase activity is ideally positioned to effect selective modulation of protein turnover. This review surveys currently available data regarding the potential role of the CSN in control of vascular function. Data potentially linking the CSN to control of regulatory proteins involved in vascular smooth muscle proliferation and to vascular smooth muscle contraction are presented with the intent of providing potentially intriguing possibilities for future investigation.
    Full-text · Article · Jun 2015 · American Journal of Cardiovascular Disease
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