Publication History View all

  • [Show abstract] [Hide abstract]
    ABSTRACT: Transgenic technologies conventionally rely on the oocyte as a substrate for genetic modification. Owing to their accessibility, however, male germ cells, including mature sperm, have material advantages for use in transgenesis. Here we have exploited lentiviruses to generate transgenic animals via the male germline. When pseudotyped lentiviral vectors encoding green fluorescent protein (GFP) were incubated with mouse spermatozoa, these sperm were highly successful in producing transgenics. Lentivirally transduced mouse spermatozoa were used in in vitro fertilization (IVF) studies, and when followed by embryo transfer, ≥42% of founders were found to be transgenic for GFP. Inverse PCR strategy for integration site analysis demonstrated integration of at least 1 or 2 copies of GFP in the transgenics, mapping to different chromosomes. GFP expression was detected in a wide range of murine tissues, including testis and the transgene was stably transmitted to a third generation of transgenic animals. This relatively simple, yet highly efficient, technique for generating transgenic animals by transducing spermatozoa with lentiviral vectors in vitro is a powerful tool for the study of fertilization/preimplantation development, vertical viral gene transmission, gene function and regulation, and epigenetic inheritance.-Chandrashekran, A., Sarkar, R., Thrasher, A., Fraser, S.E., Dibb, N., Casimir, C., Readhead, C., Winston, R. Efficient generation of transgenic mice by lentivirus-mediated modification of spermatozoa.
    The FASEB Journal 12/2013; 28(2). DOI:10.1096/fj.13-233999
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background:We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complex assembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancer remains unknown.Methods:A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) was implemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation as well as western blotting experiments were performed to further study the function of KSR1 in breast cancer.Results:Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1) phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation of DBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53.Conclusion:Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity.British Journal of Cancer advance online publication, 15 October 2013; doi:10.1038/bjc.2013.628 www.bjcancer.com.
    British Journal of Cancer 10/2013; DOI:10.1038/bjc.2013.628
  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein kinases play a pivotal role in regulating many aspects of biological processes, including development, differentiation and cell death. Within the kinome, 48 kinases (~10%) are classified as pseudokinases owing to the fact that they lack at least one conserved catalytic residue in their kinase domain. However, emerging evidence suggest that some pseudokinases, even without the ability to phosphorylate substrates, are regulators of multiple cellular signalling pathways. Among these is KSR1 (kinase suppressor of Ras 1), which was initially identified as a novel kinase in the Ras/Raf pathway. Subsequent studies showed that KSR1 mainly functions as a platform to assemble different cellular components thereby facilitating signal transduction. In the present article, we discuss recent findings regarding KSR1, indicating that it has dual activity as an active kinase as well as a pseudokinase/scaffolding protein. Moreover, the biological functions of KSR1 in human disorders, notably in malignancies, are also reviewed.
    Biochemical Society Transactions 08/2013; 41(4):1078-82. DOI:10.1042/BST20130042
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: S6 kinase 2 (S6K2) is a member of the AGC kinases super-family. Its closest homolog, S6K1, has been extensively studied along the years. However, due to the belief in the community that the high degree of identity between these two isoforms would translate in essentially identical biological functions, S6K2 has been largely neglected. Nevertheless, recent research has clearly highlighted that these two proteins significantly differ in their roles in vitro as well as in vivo. These findings are significant to our understanding of S6 kinase signaling and the development of therapeutic strategies for several diseases including cancer. Here, we will focus on S6K2 and review the protein-protein interactions and specific substrates that determine the selective functions of this kinase.
    Frontiers in Oncology 07/2013; 3:191. DOI:10.3389/fonc.2013.00191
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Steroid receptor coactivator 3 (SRC3) is an important coactivator of a number of transcription factors and is associated with a poor outcome in numerous tumours. Steroid receptor coactivator 3 is amplified in 25% of epithelial ovarian cancers (EOCs) and its expression is higher in EOCs compared with non-malignant tissue. No data is currently available with regard to the expression of SRC-3 in EOC and its influence on outcome or the efficacy of treatment. Methods: Immunohistochemistry was performed for SRC3, oestrogen receptor-α, HER2, PAX2 and PAR6, and protein expression was quantified using automated quantitative immunofluorescence (AQUA) in 471 EOCs treated between 1991 and 2006 with cytoreductive surgery followed by first-line treatment platinum-based therapy, with or without a taxane. Results: Steroid receptor coactivator 3 expression was significantly associated with advanced stage and was an independent prognostic marker. High expression of SRC3 identified patients who have a significantly poorer survival with single-agent carboplatin chemotherapy, while with carboplatin/paclitaxel treatment such a difference was not seen. Conclusion: Steroid receptor coactivator 3 is a poor prognostic factor in EOCs and appears to identify a population of patients who would benefit from the addition of taxanes to their chemotherapy regimen, due to intrinsic resistance to platinum therapy.
    British Journal of Cancer 05/2013; 108(10). DOI:10.1038/bjc.2013.199
  • [Show abstract] [Hide abstract]
    ABSTRACT: The relevance of potentially reversible post-translational modifications required for controlling cellular processes in cancer is one of the most thriving arenas of cellular and molecular biology. Any alteration in the balanced equilibrium between kinases and phosphatases may result in development and progression of various diseases, including different types of cancer, though phosphatases are relatively under-studied. Loss of phosphatases such as PTEN (phosphatase and tensin homologue deleted on chromosome 10), a known tumour suppressor, across tumour types lends credence to the development of phosphatidylinositol 3--kinase inhibitors alongside the use of phosphatase expression as a biomarker, though phase 3 trial data are lacking. In this review, we give an updated report on phosphatase dysregulation linked to organ-specific malignancies.Oncogene advance online publication, 18 March 2013; doi:10.1038/onc.2013.80.
    Oncogene 03/2013; DOI:10.1038/onc.2013.80
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer prevalence is increasing in the Middle East, partly because of increased life expectancy and adoption of western lifestyle habits. Suboptimum delivery of health care also contributes to late diagnosis and poor survival of people with cancer. Public awareness of cancer risk is frequently low and misconceptions high, thereby preventing patients from seeking treatment early and constituting a substantial barrier to improvement of cancer outcomes. Screening programmes might have low uptake in Arab populations because of social and health beliefs about cancer. This review outlines the opportunities available to Middle Eastern countries and their emerging economies to learn from global experiences in cancer care, service provision, and research partnerships. The Middle East has begun to develop several health-care transformation programmes. Qatar, in particular, has published a National Health Strategy, in which cancer is one of the main commitments; this Strategy provides the focus of this review. The development of effective health-care strategies and evidence-based medicine directly linked to innovative cancer research is needed to improve cancer care. Although the full extent of the proposed solutions are not necessarily implementable in all Middle Eastern countries, wealthy states can lead derivation of population-specific approaches that could have effects throughout the region. Key challenges are outlined-namely, human capacity and training, subspecialisation of services, building on international cancer research initiatives, and the need for earlier diagnosis and awareness in the population. Countries in the Gulf Region (ie, countries bordering the Persian Gulf, including Iran, Iraq, Kuwait, Saudi Arabia, Bahrain, Qatar, UAE, and Oman) need to address these challenges to be at the forefront of integrated cancer care and research and ensure that the latest innovations and best possible care are delivered to their populations.
    The Lancet Oncology 10/2012; 13(11). DOI:10.1016/S1470-2045(12)70461-8
  • [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to endocrine therapy in breast cancer is common. With the aim of discovering new molecular targets for breast cancer therapy, we have recently identified LMTK3 as a regulator of the estrogen receptor-alpha (ERα) and wished to understand its role in endocrine resistance. We find that inhibition of LMTK3 in a xenograft tamoxifen (Tam)-resistant (BT474) breast cancer mouse model results in re-sensitization to Tam as demonstrated by a reduction in tumor volume. A whole genome microarray analysis, using a BT474 cell line, reveals genes significantly modulated (positively or negatively) after LMTK3 silencing, including some that are known to be implicated in Tam resistance, notably c-MYC, HSPB8 and SIAH2. We show that LMTK3 is able to increase the levels of HSPB8 at a transcriptional and translational level thereby protecting MCF7 cells from Tam-induced cell death, by reducing autophagy. Finally, high LMTK3 levels at baseline in tumors are predictive for endocrine resistance; therapy does not lead to alteration in levels, whereas in patient's plasma samples, acquired LMTK3 gene amplification (copy number variation) was associated with relapse while receiving Tam. In aggregate, these data support a role for LMTK3 in both innate (intrinsic) and acquired (adaptive) endocrine resistance in breast cancer.Oncogene advance online publication, 6 August 2012; doi:10.1038/onc.2012.343.
    Oncogene 08/2012; DOI:10.1038/onc.2012.343
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The CCAAT/enhancer binding protein delta (CEBPδ) is a member of a highly conserved family of basic region leucine zipper transcription factors. It has properties consistent with a tumour suppressor; however, other data suggest that CEBPδ may be involved in the metastatic process. We analysed the expression of CEBPδ and the methylation status of the CpG island in human breast cancer cell lines, in 107 archival cases of primary breast cancer and in two series of metastatic breast cancers using qPCR and pyrosequencing. Expression of CEBPδ is downregulated in primary breast cancer by site-specific methylation in the CEBPδ CpG island. Expression is also downregulated in 50% of cases during progression from primary carcinoma to metastatic lesions. The CEBPδ CpG island is methylated in 81% metastatic breast cancer lesions, while methylation in the CEBPδ CpG island in primary cancers is associated with increased risk of relapse and metastasis. CCAAT/enhancer binding protein delta CpG island methylation is associated with metastasis in breast cancer. Detection of methylated CEBPδ genomic DNA may have utility as an epigenetic biomarker of primary breast carcinomas at increased risk of relapse and metastasis.
    British Journal of Cancer 07/2012; 107(4):732-8. DOI:10.1038/bjc.2012.308
  • The Lancet Oncology 06/2012; 13(7):653-4. DOI:10.1016/S1470-2045(12)70245-0
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.
View all

Top publications last week

Journal of the American Academy of Child & Adolescent Psychiatry 07/2006; 45(6):691-9. DOI:10.1097/01.chi.0000215325.13058.9d
Proteomics 02/2013; 13(3-4). DOI:10.1002/pmic.201200397