Article

P21 in cancer: Intricate networks and multiple activities

Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
Nature Reviews Cancer (Impact Factor: 29.54). 06/2009; 9(6):400-14. DOI: 10.1038/nrc2657
Source: PubMed

ABSTRACT One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21WAF1/Cip1) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.

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Available from: Tarek Abbas, Sep 29, 2014
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    • "Considering that cell cycle arrest in G2, after DNA damage, may activate a process known as cell-cycle adaptation, in which cells reactivate cyclin-dependent kinase 2 complexes and proceed with mitosis, despite the presence of unrepaired damaged DNA, it is possible that U87 cells activate this process justifying the maintenance of the proliferation rate and of the cell cycle [47] [48]. Moreover considering that (1) cell cycle progression is dependent on P21, which plays a critical role in arresting the cell cycle in G1 and G2 after DNA damage [49]; (2) the PKC activation upregulates the P21 protein [50]; and (3) the treatment of U118 cells with TMX plus TMZ significantly reduced the p-PKC-pan expression in this study, it is possible that the reduction of p-PKC-pan is involved in down-regulation of P21 expression, and as a result, the cell cycle progresses normally in some cells. We are now evaluating the level of P21 protein in the presence of TMX and/or TMZ. "
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    ABSTRACT: Glioblastoma (GBM) is a highly proliferative, angiogenic grade IV astrocytoma that develops resistance to the alkylating agents used in chemotherapy, such as temozolomide (TMZ), which is considered the gold standard. The mean survival time for GBM patients is approximately 12months, increasing to 14.6months after TMZ treatment. The resistance of GBM to chemotherapy seems to be associated to genetic alterations and to the constitutive activation of several signalling pathways. Therefore, the combination of different drugs with different mechanisms of action may contribute to circumvent the chemoresistance of glioma cells. Here we describe the potential synergistic behavior of the therapeutic combination of tamoxifen (TMX), a known inhibitor of PKC, and TMZ in GBM. We used two GBM cell lines incubated in absence and presence of TMX and/ or TMZ, and measured cell viability, proliferation, apoptosis, cell cycle, migration ability, cytoskeletal organization and the phosphorylated amount of the p-PKC-pan. The combination of low doses of TMX with increasing doses of TMZ shows an increased antiproliferative and apoptotic effect compared to the effect with TMX alone. The combination of TMX and TMZ seems to potentiate the effect of each other. These alterations seem to be associated to a decrease in the phosphorylation status of PKC. We emphasize that TMX is an inhibitor of the p-PKC-pan and that these combination is more effective in the reduction of proliferation and in the increase of apoptosis than each drug alone, which presents a new therapeutic strategy in GBM treatment. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - General Subjects 12/2014; 1850(4). DOI:10.1016/j.bbagen.2014.12.022 · 3.83 Impact Factor
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    • "More recently it has been reported that p57 integrates stress signals into cell cycle progression to promote cell survival in response to various types of injuries, including oxidative stress (Joaquin et al., 2012). On the other hand, p21 is transcriptionally induced by the tumor suppressor p53 after DNA damage (Abbas and Dutta, 2009) or by TGFb through the SMAD transcription factors (Schmierer and Hill, 2007). In Vero cells treated with Mix 100, p53 gene expression tended to be upregulated although did not meet the log 2 cut-off ratio of 0.8. "
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    ABSTRACT: Butylated hydroxyanisole and propylparaben are phenolic preservatives commonly used in food, pharmaceutical and personal care products. Both chemicals have been subjected to extensive toxicological studies, due to the growing concern regarding their possible impacts on environmental and human health. However, the cytotoxicity and underlying mechanisms of co-exposure to these compounds have not been explored. In this study, a set of relevant cytotoxicity endpoints including cell viability and proliferation, oxidative stress, DNA damage and gene expression changes were analyzed to assess whether the antioxidant butylated hydroxyanisole could prevent the pro-oxidant effects caused by propylparaben in Vero cells. We demonstrated that binary mixtures of both chemicals induce greater cytotoxic effects than those reported after single exposureto each compound. Simultaneous treatment with butylated hydroxyanisole and propylparaben caused G0/G1 cell cycle arrest as a result of enhanced generation of oxidative stress and DNA double strand breaks. DNA microarray analysis revealed that a cross-talk between transforming growth factor beta (TGFβ) and ataxia-telangiectasia mutated kinase (ATM) pathways regulates the response of Vero cells to the tested compounds in binary mixture. Our findings indicate that butylated hydroxyanisole potentiates the pro-oxidant effects of propylparaben in cultured mammalian cells and provide useful information for their safety assessment.
    Food and Chemical Toxicology 07/2014; 72. DOI:10.1016/j.fct.2014.07.031 · 2.90 Impact Factor
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    • "Solid arrows indicate positive control. Dotted arrows indicate possible pathway but not yet shown to be involved in ethanol-dependent signal transduction or pathways with only limited data to support their existence which might account for its paradoxical oncogenic activity, p21 might also promote apoptosis in response to certain cellular stresses (Abbas and Dutta 2009). p21 was first identified as a mediator of p53 tumor suppressor , but it has been recently found that p21 is stimulated by many pathways that are p53 independent (Thaler et al. 2009). "
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    ABSTRACT: Ethanol exposure has deleterious effects on the central nervous system. Although several mechanisms for ethanol-induced damage have been suggested, the precise mechanism underlying ethanol-induced neuronal cell death remains unclear. Recent studies indicate that the p75 neurotrophin receptor (p75NTR) has a critical role in the regulation of neuronal survival. This study was designed to examine the role of p75NTR in ethanol-induced apoptotic signaling in neuroblastoma cells. Ethanol caused highly increased level of p75NTR expression. The use of small interfering RNA to inhibit p75NTR expression markedly attenuated ethanol-induced cell cycle arrest and apoptosis. DNA binding activity of Sp1 was increased by ethanol, whereas inhibition of Sp1 activity by mithramycin, a Sp1 inhibitor, or short hairpin RNA suppressed ethanol-induced p75NTR expression. In addition, inhibitors of casein kinase 2 (CK2) and extracellular signal-regulated kinase (ERK) augmented ethanol-induced p75NTR expression. Our results also demonstrate that inhibition of ERK and CK2 caused a further increase in the activation of the p75NTR proximal promoter induced by ethanol. This increased activation was partially suppressed by the deletion of the Sp1 binding sites. These results suggest that Sp1-mediated p75NTR expression is regulated at least in part by ERK and CK2 pathways. The present study also showed that treatment with ethanol resulted in significant increases in the expression of p21, but not the levels of p53 and p53 target genes such as Bax, Puma, and Bcl-2. Furthermore, the inhibition of p75NTR expression or Sp1 activity suppressed ethanol-induced p21 expression, cell cycle arrest, and apoptosis. These data suggest that ethanol increases p75NTR expression, and CK2 and ERK signaling inversely regulate Sp1-mediated p75NTR expression in ethanol-treated neuroblastoma cells. Thus, our study provides more insight into the mechanisms underlying ethanol actions.
    Cell Biology and Toxicology 09/2013; 29(5). DOI:10.1007/s10565-013-9260-3 · 1.97 Impact Factor
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Questions & Answers about this publication

  • Go J Yoshida added an answer in Kinase:
    What is the relation between p21 and p21-associated kinase?

    I repeatedly stumble over p21 and p21-associated kinase, but somehow never in the same publication. What, if any, is their relation to each other? Why are they associated by name? Any reference? Thanks.

    Go J Yoshida · Tokyo Medical and Dental University

    p21 responds to a variety of stimuli to promote growth-inhibitory activities that depend primarily on its ability to inhibit the kinase activity of cyclin-dependent kinase 2 (CDK2). p21-induced cell cycle arrest also depends on its ability to inhibit CDK1. p21 can inhibit cellular proliferation independent of CDK2 inhibition by inhibiting proliferating cell nuclear antigen (PCNA), which is required for S phase progression. Some of the anti-proliferative activities of p21 rely on its multiple protein–protein interactions and its ability to regulate gene transcription. The various physiological responses triggered by p21 are interconnected. For example, cell cycle arrest induced by p21 promotes DNA repair by allowing sufficient time for the damaged DNA to be repaired before it is passed to daughter cells and is a major route by which p21 exerts its anti-apoptotic activities. Similarly, the ability of p21 to regulate gene expression is important in promoting cellular senescence. The effect of p21 on gene transcription is generally inhibitory, but p21 can also activate gene transcription under certain conditions.