Abbas T, Dutta Ap21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9: 400-414

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: 37.4). 06/2009; 9(6):400-14. DOI: 10.1038/nrc2657
Source: PubMed


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.

Download full-text


Available from: Tarek Abbas, Sep 29, 2014
49 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "Upon NEK9 KD in p53-deficient cells, but not p53 WT cells, two crucial regulators of the cell cycle were differentially regulated: p21 was up-regulated, and MAPK14 (also known as p38α) was down-regulated (Fig. 4F). These two factors control the cell cycle regardless of TP53 status2223242526. However, in cancer cells with p53 mutations, NEK9 KD modulated the expression of both factors, leading to cell-cycle arrest with characteristics of senescence. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dysfunction of the p53 network is a major cause of cancer development, and selective elimination of p53-inactivated cancer cells therefore represents an ideal therapeutic strategy. In this study, we performed a microRNA target screen that identified NEK9 (NIMA-related kinase 9) as a crucial regulator of cell-cycle progression in p53-inactivated cancer cells. NEK9 depletion selectively inhibited proliferation in p53-deficient cancer cells both in vitro and in vivo. The resultant cell-cycle arrest occurred predominantly in G1 phase, and exhibited senescence-like features. Furthermore, NEK9 repression affected expression of a broad range of genes encoding cell-cycle regulators and factors involved in mRNA processing, suggesting a novel role for NEK9 in p53-deficient cells. Lung adenocarcinoma patients with positive staining for NEK9 and mutant p53 proteins exhibited significantly poorer prognoses, suggesting that expression of both proteins promotes tumor growth. Our findings demonstrate that a novel NEK9 network regulates the growth of cancer cells lacking functional p53.
    Scientific Reports 08/2014; 4:6111. DOI:10.1038/srep06111
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
Show more

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

    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.

    + 1 more attachment