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    ABSTRACT: Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the specific removal of mitochondria via mitophagy. Mitochondria-deficient cells were resistant to the mitochondrial pathway of apoptosis, but efficiently died via tumor necrosis factor (TNF)-induced, RIPK3-dependent programmed necrosis or as a result of direct oligomerization of RIPK3. Although the ROS scavenger butylated hydroxyanisole (BHA) delayed TNF-induced necroptosis, it had no effect on necroptosis induced by RIPK3 oligomerization. Furthermore, although TNF-induced ROS production was dependent on mitochondria, the inhibition of TNF-induced necroptosis by BHA was observed in mitochondria-depleted cells. Our data indicate that mitochondrial ROS production accompanies, but does not cause, RIPK3-dependent necroptotic cell death.
    Cell Reports 11/2013;
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    ABSTRACT: TAL1 is an important regulator of hematopoiesis and its expression is tightly controlled despite complexities in its genomic organization. It is frequently misregulated in T-cell acute lymphoblastic leukemia (T-ALL), often due to deletions between TAL1 and the neighbouring STIL gene. To better understand the events that lead to TAL1 expression in hematopoiesis and in T-ALL, we studied looping interactions at the TAL1 locus. In TAL1 expressing erythroid cells, the locus adopts a looping "hub" which brings into close physical proximity all known TAL1 cis-regulatory elements including CTCF-bound insulators. Loss of GATA1 results in disassembly of the hub and loss of CTCF/RAD21 from one of its insulators. Genes flanking TAL1 are partly dependent on hub integrity for their transcriptional regulation. We identified looping patterns unique to TAL1 expressing T-ALL cells, and, intriguingly, loops occurring between the TAL1 and STIL genes at the common TAL1/STIL breakpoints found in T-ALL. These findings redefine how TAL1 and neighbouring genes communicate within the nucleus, and indicate that looping facilitates both normal and aberrant TAL1 expression and may pre-dispose to structural rearrangements in T-ALL. We also propose that GATA1-dependent looping mechanisms may facilitate the conservation of TAL1 regulation despite cis-regulatory remodelling during vertebrate evolution.
    Blood 11/2013;
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    ABSTRACT: Sirtuins comprise a family of genes involved in cellular stress, survival and damage responses. They have been implicated in a range of diseases including cancer, with most information pertaining to their function in tumourigenesis being derived from in vitro studies, or model organisms. Their putative roles as tumour suppressors or tumour promoters remain to be validated in vivo. Little is known about their role in breast tumourigenesis. We sought to evaluate the seven sirtuin family members (SIRT1-7) in a human breast cancer cohort, in relation to clinico-pathological features and outcome of the disease. Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in 392 oestrogen receptor (ER+ve) and 153 ER-ve breast tumour samples. SIRT1-7 transcriptional levels were assessed in normal (n=25), non-malignant (n=73) and malignant (n=70) breast tissue using Relative Quantitative Real Time PCR. Statistical analyses determined if SIRT1-7 transcription or protein expression was associated with clinical parameters or outcome. In ER-ve tumours, high protein levels of nuclear SIRT2 were associated with reduced time to recurrence and disease-specific death. This association was only observed in Grade 3 tumours. In the ER+ve cohort, high SIRT2 nuclear levels were associated with shorter disease-free survival and time to recurrence whilst on Tamoxifen, in patients with Grade 3 tumours. Conversely, in Grade 2 tumours, high SIRT2 levels were associated with increased time to recurrence. Our data suggest that SIRT2 is the sirtuin predominantly involved in breast tumourigenesis and prognosis. It indicates that SIRT2 acts as a tumour suppressor or tumour promoter dependent upon breast tumour grade.
    European journal of cancer (Oxford, England: 1990) 10/2013;
  • Blood 10/2013; 122(17):2926-8.
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    ABSTRACT: The histone methyltransferase Ezh2, a component of the polycomb group complex, is vital for stem cell development, including hematopoiesis. Its primary function, to deposit the histone mark H3K27me3, promotes transcriptional repression. The activity of EZH2 influences cell fate regulation, namely the balance between self-renewal and differentiation. The contribution of aberrant EZH2 expression to tumorigenesis by directing cells towards a cancer stem cell (CSC) state is increasingly recognized. However, its role in hematological malignancies is complex. Point mutations, resulting in gain-of-function, as well as inactivating mutations, reported in lymphoma and leukemia respectively, suggest that EZH2 may serve a dual purpose as an oncogene and tumor suppressor gene. The reduction of CSC self-renewal via Ezh2 inhibition offers a potentially attractive therapeutic approach to counter the aberrant activation found in lymphoma and leukemia. The discovery of small molecules that specifically inhibit Ezh2 raises the exciting possibility of exploiting the oncogenic addiction of tumor cells towards this protein. However, interference with the tumor suppressor role of wild-type EZH2 must be avoided. This review examines the role of Ezh2 in normal and malignant hematopoiesis and recent developments in harnessing the therapeutic potential of Ezh2 inhibition.Leukemia accepted article preview online, 7 October 2013. doi:10.1038/leu.2013.288.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2013;
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    ABSTRACT: Autophagy is a process that takes place in all mammalian cells and ensures homoeostasis and quality control. The term autophagy [self (auto)-eating (phagy)] was first introduced in 1963 by Christian de Duve, who discovered the involvement of lysosomes in the autophagy process. Since then, substantial progress has been made in understanding the molecular mechanism and signalling regulation of autophagy and several reviews have been published that comprehensively summarize these findings. The role of autophagy in cancer has received a lot of attention in the last few years and autophagy modulators are now being tested in several clinical trials. In the present chapter we aim to give a brief overview of recent findings regarding the mechanism and key regulators of autophagy and discuss the important physiological role of mammalian autophagy in health and disease. Particular focus is given to the role of autophagy in cancer prevention, development and in response to anticancer therapy. In this regard, we also give an updated list and discuss current clinical trials that aim to modulate autophagy, alone or in combination with radio-, chemo- or targeted therapy, for enhanced anticancer intervention.
    Essays in Biochemistry 09/2013; 55(1):133-51.
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    ABSTRACT: Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway (senescence-associated secretory phenotype). Cellular senescence is also a tumor suppressor mechanism, to which both proliferation arrest and senescence-associated secretory phenotype are thought to contribute. The melanocytes within benign human nevi are a paradigm for tumor-suppressive senescent cells in a premalignant neoplasm. Here a comparison of proliferating and senescent melanocytes and melanoma cell lines by RNA sequencing emphasizes the importance of senescence-associated proliferation arrest in suppression of transformation. Previous studies showed that activation of the Wnt signaling pathway can delay or bypass senescence. Consistent with this, we present evidence that repression of Wnt signaling contributes to melanocyte senescence in vitro. Surprisingly, Wnt signaling is active in many senescent human melanocytes in nevi, and this is linked to histological indicators of higher proliferative and malignant potential. In a mouse, activated Wnt signaling delays senescence-associated proliferation arrest to expand the population of senescent oncogene-expressing melanocytes. These results suggest that Wnt signaling can potentiate nevogenesis in vivo by delaying senescence. Further, we suggest that activated Wnt signaling in human nevi undermines senescence-mediated tumor suppression and enhances the probability of malignancy.
    Proceedings of the National Academy of Sciences 09/2013;
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    ABSTRACT: Chronic myeloid leukaemia (CML) stem cells are not dependent on BCR-ABL kinase for their survival suggesting that kinase-independent mechanisms must contribute to their persistence. We observed that CML stem/progenitor cells (SPCs) produce tumour necrosis factor-alpha (TNF-α) in a kinase-independent fashion and at higher levels relative to their normal counterparts. We therefore investigated the role of TNF-α and found that it supports survival of CML SPCs by promoting NFκB/p65 pathway activity and expression of the interleukin-3 and granulocyte/macrophage-colony stimulating factor common β-chain receptor. Furthermore, we demonstrate that in CML SPCs inhibition of autocrine TNF-α signalling via a small molecule TNF-α inhibitor induces apoptosis. Moreover TNF-α inhibition combined with nilotinib induces significantly more apoptosis relative to either treatment alone and a reduction in the absolute number of primitive quiescent CML stem cells. These results highlight a novel survival mechanism of CML SPCs and suggest a new putative therapeutic target for their eradication.
    Blood 09/2013;
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    ABSTRACT: The insensitivity of Chronic Myeloid Leukaemia (CML) stem cells to Tyrosine Kinase Inhibitor (TKI) treatment is now believed to be the main reason for disease persistence experienced in patients. It has been shown that autophagy, an evolutionarily conserved catabolic process that involves degradation of unnecessary or harmful cellular components via lysosomes, is induced following TKI treatment in CML cells. Of clinical importance, autophagy inhibition, using the anti-malarial drug hydroxychloroquine (HCQ), sensitised CML cells, including primitive CML stem cells, to TKI treatment. In this review we discuss the role of autophagy in the maintenance and survival of stem cells in more detail, with a focus on its role in survival of CML stem cells and the possibility to inhibit this pathway as a way to eliminate persistent CML stem cells in vitro and in patients.
    Current cancer drug targets 08/2013;
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    ABSTRACT: Tribbles are members of the pseudokinase family of proteins, with no associated kinase activity detectable to date. As tribbles appear not to function as kinases, there has been debate surrounding their functional classification. Tribbles have been proposed to function as adaptor molecules facilitating degradation of their target proteins. Tribbles have also been proposed to mediate signalling changes to MAPK (mitogen-activated protein kinase) cascades and also to function as decoy kinases interfering with the activity of known kinases. The present review discusses the functionally divergent roles of tribbles as molecular adaptors mediating degradation, changes to signalling cascades and action as decoy kinases.
    Biochemical Society Transactions 08/2013; 41(4):1096-100.
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