• Molecular and Cellular Mechanisms of Action of Tumour Suppressor GAS5 LncRNA

      Pickard, Mark R.; Williams, Gwyn T.; Keele University (MDPI, 2015-07-07)
      It is increasingly recognised that lncRNAs play essential regulatory roles in fundamental biological processes and, consequently, that their dysregulation may contribute to major human diseases, including cancer. Better understanding of lncRNA biology may therefore offer new insights into pathogenetic mechanisms and thereby offer novel opportunities for diagnosis and therapy. Of particular interest in this regard is GAS5 lncRNA, which is down-regulated in multiple cancers, with expression levels related to both clinico-pathological characteristics and patient prognosis. Functional studies have further shown that GAS5 lncRNA both inhibits the proliferation and promotes the apoptosis of multiple cell types, and that together these cellular mechanisms of action are likely to form the basis of its tumour suppressor action. At the same time, advances have been made in our understanding of the molecular mechanisms of GAS5 lncRNA action in recent years, including riborepression of certain steroid hormone receptors and sequestration of miR-21, impacting key regulatory pathways of cell survival. Overall this accumulating knowledge has the potential to improve both the diagnosis and treatment of cancer, and ultimately patient outcome.
    • Retroviral insertional mutagenesis implicates E3 ubiquitin ligase RNF168 in the control of cell proliferation and survival

      Kizilors, Aytug; Pickard, Mark R.; Schulte, Cathleen E.; Yacqub-Usman, Kiren; McCarthy, Nicola J.; Gan, Shu-Uin; Darling, David; Gäken, Joop; Williams, Gwyn T.; Farzaneh, Farzin; Kings College London; Keele University; University of Chester; University of Nottingham; National University of Singapore (Portland Press, 2017-08-14)
      The E3 ubiquitin ligase RNF168 is a ring finger protein that has previously been identified to play an important regulatory role in the repair of double-strand DNA breaks. In the present study, an unbiased forward genetics functional screen in mouse granulocyte/ macrophage progenitor cell line FDCP1 has identified E3 ubiquitin ligase RNF168 as a key regulator of cell survival and proliferation. Our data indicate that RNF168 is an important component of the mechanisms controlling cell fate, not only in human and mouse haematopoietic growth factor-dependent cells, but also in the human breast epithelial cell line MCF-7. These observations therefore suggest that RNF168 provides a connection to key pathways controlling cell fate, potentially through interaction with PML nuclear bodies and/or epigenetic control of gene expression. Our study is the first to demonstrate a critical role for RNF168 in the in the mechanisms regulating cell proliferation and survival, in addition to its well-established role in DNA repair.