Cell-cyclin inhibitors: Three families united by common cause

Laboratory of Cell Cycle Regulation, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Gene (Impact Factor: 2.14). 05/2000; 247(1-2):1-15. DOI: 10.1016/S0378-1119(00)00092-5
Source: PubMed


In the cellular program leading to DNA synthesis, signals that drive cells into S-phase converge at the level of CDK activity. The products of at least three different gene families, Ink4, Cip/Kip and the pRb pocket-protein family, suppress S-phase entry. Ink4 proteins act by antagonizing the formation and activation of cyclin D-CDK4 complexes, of which the ultimate downstream target as related to S-phase entry appears to be pRb. Cip/Kip inhibitors impinge upon that pathway by inhibiting CDK2 kinases that participate in the inactivation of pRb and, like cyclin E, may also have roles independent of pRb. How the activities of these three classes of proteins are coordinated remains obscure. In recent years, development of mouse models has accelerated the elucidation of this complex network, showing roles that are sometimes cooperative and sometimes overlapping. We will discuss the interrelationships between Cip/Kip inhibitors and the components of the pRb pathway, and how their activities ultimately regulate cell proliferation.

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    • "A non-coding antisense RNA named ANRIL (antisense noncoding RNA in the INK4 locus, CDKN2BAS) has also been found within the human Ink4a/Arf locus [21]. Whilst p16 Ink4a and p15 Ink4b are potent cell cycle inhibitors through binding to CDK4,6/cy- clin D kinases [22], ARF mainly exerts a proapoptotic activity via the inhibition of MDM2, an ubiquitin-ligase that destabilises the tumour suppressor p53 [23]. The mechanisms coupling the Ink4/Arf locus variants , its gene activity and glucose metabolism are very poorly known. "
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    ABSTRACT: Single nucleotide polymorphisms near the Ink4/Arf locus have been associated with type-2 diabetes mellitus. Previous studies indicate a protective role of the locus in the carbohydrate metabolism derangement associated with aging in wild-type (WT) mice. The present study demonstrates that the increased Ink4/Arf locus expression in 1-year-old mice, partially-deficient for the insulin receptor substrate (IRS)2 (Irs2+/-SuperInk4/Arf mice) ameliorates hepatic steatosis, inflammation and insulin resistance. Irs2+/-SuperInk4/Arf mice displayed improved glucose tolerance and insulin sensitivity compared with Irs2+/- mice which were glucose intolerant and insulin resistant compared with age-matched WT mice. These changes in Irs2+/- mice were accompanied by enhanced hepatic steatosis, proinflammatory macrophage phenotype, increased Ly6C(hi)-monocyte percentage, T-lymphocyte activation and MCP1 and TNF-α cytokine levels. In Irs2+/-SuperInk4/Arf mice, steatosis and inflammatory parameters were markedly reduced and similar to those of WT counterparts. In vivo insulin signalling also revealed reduced activation of the IRS/AKT-dependent signalling in Irs2+/- mice. This was restored upon increased locus expression in Irs2+/-SuperInk4/Arf mice which display similar activation levels as those for WT mice. In vivo treatment of Irs2+/-SuperInk4/Arf mice with TNF-α diminished insulin canonical IRS/AKT-signalling and enhanced the stress SAPK/JNK-phosphoSer307IRS1-pathway suggesting that cytokine levels might potentially affect glucose homeostasis through changes in these insulin-signalling pathways. Altogether, these results indicate that enhanced Ink4/Arf locus expression restores glucose homeostasis and that this is associated with diminished hepatic steatosis and inflammation in mice with insulin resistance. Therefore, pharmacological interventions targeted to modulate the Ink4/Arf locus expression could be a tentative therapeutic approach to alleviate the inflammation associated with insulin resistance. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; 1852(9). DOI:10.1016/j.bbadis.2015.05.013 · 4.66 Impact Factor
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    • "The CDK activity is negatively regulated by the interaction with specific CDK inhibitory proteins (CKIs) like p27Kip1. [29], [30] We showed that cyclin-dependent kinase inhibitor p27Kip1 was highly expressed in quiescent cells and high levels of p27Kip1 protein expression in RanGAP1 deficient cells. This is in accordance with findings from a balloon angioplasty study in rat arteries showing the induction of p27Kip1 in vascular SMCs and the contribution of p27Kip1 upregulation in the re-establishment of the quiescent phenotype. "
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    ABSTRACT: Differentiation and dedifferentiation, accompanied by proliferation play a pivotal role for the phenotypic development of vascular proliferative diseases (VPD), such as restenosis. Increasing evidence points to an essential role of regulated nucleoporin expression in the choice between differentiation and proliferation. However, whether components of the Ran GTPase cycle, which is of pivotal importance for both nucleocytoplasmic transport and for mitotic progression, are subject to similar regulation in VPD is currently unknown. Here, we show that differentiation of human coronary artery smooth muscle cell (CASMC) to a contractile phenotype by stepwise serum depletion leads to significant reduction of RanGAP1 protein levels. The inverse event, dedifferentiation of cells, was assessed in the rat carotid artery balloon injury model, a well-accepted model for neointima formation and restenosis. As revealed by temporospatial analysis of RanGAP1 expression, neointima formation in rat carotid arteries was associated with a significant upregulation of RanGAP1 expression at 3 and 7 days after balloon injury. Of note, neointimal cells located at the luminal surface revealed persistent RanGAP1 expression, as opposed to cells in deeper layers of the neointima where RanGAP1 expression was less or not detectable at all. To gain first evidence for a direct influence of RanGAP1 levels on differentiation, we reduced RanGAP1 in human coronary artery smooth muscle cells by siRNA. Indeed, downregulation of the essential RanGAP1 protein by 50% induced a differentiated, spindle-like smooth muscle cell phenotype, accompanied by an upregulation of the differentiation marker desmin. Reduction of RanGAP1 levels also resulted in a reduction of mitogen induced cellular migration and proliferation as well as a significant upregulation of the cyclin-dependent kinase inhibitor p27KIP1, without evidence for cellular necrosis. These findings suggest that RanGAP1 plays a critical role in smooth muscle cell differentiation, migration and proliferation in vitro and in vivo. Appropriate modulation of RanGAP1 expression may thus be a strategy to modulate VPD development such as restenosis.
    PLoS ONE 07/2014; 9(7):e101519. DOI:10.1371/journal.pone.0101519 · 3.23 Impact Factor
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    • "HDAC1 is a histone deacetylase that is able to inhibit the expression of cell cycle genes such as p21. By ubiquitination of HDAC1, CHFR is able to reverse HDAC1-induced repression of p21 and thereby restore the p21-G1 checkpoint [28, 30, 31]. Interestingly, CHFR was also shown to inhibit invasiveness and metastatic potential caused by HDAC1 expression by the regulation of metastasis suppressors, KAI1 and E-cadherin [28]. "
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    ABSTRACT: Novel insights in the biology of cancer have switched the paradigm of a "one-size-fits-all" cancer treatment to an individualized biology-driven treatment approach. In recent years, a diversity of biomarkers and targeted therapies has been discovered. Although these examples accentuate the promise of personalized cancer treatment, for most cancers and cancer subgroups no biomarkers and effective targeted therapy are available. The great majority of patients still receive unselected standard therapies with no use of their individual molecular characteristics. Better knowledge about the underlying tumor biology will lead the way toward personalized cancer treatment. In this review, we summarize the evidence for a promising cancer biomarker: checkpoint with forkhead and ring finger domains (CHFR). CHFR is a mitotic checkpoint and tumor suppressor gene, which is inactivated in a diverse group of solid malignancies, mostly by promoter CpG island methylation. CHFR inactivation has shown to be an indicator of poor prognosis and sensitivity to taxane-based chemotherapy. Here we summarize the current knowledge of altered CHFR expression in cancer, the impact on tumor biology and implications for personalized cancer treatment.
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