Article

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

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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    • "However, it also promotes tumorigenesis in many types of cancer including HCC, where increased P21 expression has been linked with disease development in patients with chronic liver diseases[23,24]. The oncogenic activity of P21 depends on its cytoplasmic retention and stability following its phosphorylation on Thr145 and Ser146 by AKT, downstream of growth factor sig- naling[25,26]. A recent study has reported that SOCS1 repressed P21 expression and oncogenic functions in hepatocytes, both in vivo and in cellulo[27]. "
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    ABSTRACT: The Suppressor Of Cytokine Signaling 1 (SOCS1) has been extensively investigated in immune cells where it works as a potent inhibitor of inflammation by negative feedback regulation of the cytokine-activated JAK–STAT signaling pathways. SOCS1 is also recognized as a tumor suppressor in numerous cancers and its critical functional relevance in non-immune cells, including epithelial cells, has just begun to emerge. Most notably, conflicting results from clinical and experimental studies suggest that SOCS1 may function as either a tumor suppressor or a tumor promoter, in a cell context-dependent manner. Here, we present an overview of the mechanisms underlying SOCS1 function as a tumor suppressor and discuss the emerging evidences of SOCS1 activity as an oncogene.
    Full-text · Article · Jan 2016 · Cytokine
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    • "Significantly upregulated stress and DNA-damage-related transcripts included known gene targets of the transcription factors HIF1α and/or p53, such as GDF15, BNIP3, CDKN1A ( p21), NDRG1, GADD45A, GADD45G, MIF, DDIT4, STK11 (LKB1) and OSGIN1 (Table S4). These pathways might have been activated through two routes – stabilization of HIF1α due to altered Fe ion metabolism and/or increased ROS accumulation, or ROSinduced DNA damage leading to stabilization of p53 (Chepelev and Willmore, 2011;Mole, 2010; Reinhardt and Schumacher, 2012).The upregulation of CDKN1A, GADD45A, GADD45G and DDIT4 suggests that NAF-1(−) cells could undergo cell cycle arrest (Table S4) (Abbas and Dutta, 2009;Salvador et al., 2013;Sofer et al., 2005). In addition, the increased expression of BNIP3, DDIT4 and OSGIN1 might support the notion of activation of apoptosis (Table S4) (Burton and Gibson, 2009;Hu et al., 2012;Mellor and Harris, 2007;Yao et al., 2008). "
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    ABSTRACT: Maintaining iron and reactive oxygen species homeostasis is essential for cellular function, mitochondrial integrity and the regulation of cell death pathways, and is recognized as a key process underlying the molecular basis of aging and various diseases such as diabetes, neurodegenerative diseases, and cancer. Nutrient-deprivation autophagy factor 1 (NAF-1) belongs to a newly discovered class of iron-sulfur proteins localized to the outer mitochondrial membrane and the ER. It has been implicated in regulating iron homeostasis, as well as the activation of autophagy via interaction with BCL-2. Here we show that shRNA suppression of NAF-1 results in the activation of apoptosis in epithelial breast cancer cells and xenograft tumors. Suppression of NAF-1 resulted in increased iron uptake into cells, a metabolic shift that rendered cells more susceptible to a glycolysis inhibitor, and the activation of cellular stress pathways associated with HIF1α. Our studies suggest that NAF-1 is a major player in the metabolic regulation of breast cancer cells through its effects on cellular iron distribution, mitochondrial metabolism and the induction of apoptosis.
    Full-text · Article · Nov 2015 · Journal of Cell Science
    • "Earlier studies support the view that p21 suppresses tumors by promoting cell cycle arrest in response to various stimuli[44,45]. While p21 regulation is often compromised in human cancers, its continuous expression, depending on the cellular context, suggests that it can act as either a tumor suppressor or an onco- gene[43]. Deletion of p21 enhanced the rate of Ras-or c-Myc-induced tumorigenesis, and was associated with gene expression profiles and immunohistochemical features of EMT[29], consistent with our finding of enhanced migration with activin-induced p21 downregulation. "
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    ABSTRACT: Background: Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGF beta or activin-induced metastatic phenotype of colon cancer. Method: Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays. Results: In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGF beta/MEK/ERK pathway activation. Activin, but not TGF beta, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGF beta increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGF beta induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling. Conclusion: Although activin and TGF beta share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGF beta ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGF beta family receptors.
    No preview · Article · Oct 2015 · Molecular Cancer
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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

    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.

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