Raptis, Leda H - Queen's University - Department of Biomedical and Molecular Sciences

个人简介

Signal transduction in neoplastic transformation and adipocytic differentiation. a) Ras, b) Stat3 Signalling from cell to cell adhesion molecules Electroporation of adherent cells in situ

研究领域

Signal transduction in transformation and adipocytic differentiation. a) Ras, b) Stat3 Electroporation of adherent cells in situ Details of Research Interests: Cellular interactions with neighbouring cells profoundly influence a variety of signalling events involved in mitogenesis, survival and differentiation. Unlike tissue-culture cells, cells in a tumor have extensive opportunities for adhesion to their neighbours in a three-dimensional structure, therefore in the study of these processes it is important to take into account the effect of surrounding cells. Cadherins recently emerged as a group of cell-cell adhesion molecules playing a key role in the regulation of signalling events as well as the maintenance of tissue architecture. Our lab has recently demonstrated that engagement of E-cadherin can lead to a dramatic increase in the activity of Stat3, a protein often abnormally activated in cancer. Most importantly, Stat3 activation was independent from a number of tyrosine kinases, including the Src family, IGF1-R, EGFR and Fer, often activated in many cancers. This novel pathway could be a promising target in the treatment of cancers which may be independent from most tyrosine kinase oncogenes known to be activated in many cancers. Our recent work deals with the elucidation of this novel mechanism. We are using two different approaches: 1. Downregulation of expression of specific cellular genes through the introduction of an anti-message, dominant-negative mutants or siRNA, to demonstrate the overall involvement of a gene product. 2. Introduction of peptides corresponding to the proteins' point(s) of contact using a novel apparatus, to more specifically pinpoint the areas involved. The reduction in the activity of a signal transducer can demonstrate its overall involvement in the transmission of a signal. To further examine its role, it is imperative to more finely pinpoint the in vivo interactions of different areas of the protein with other members of the cascade. To achieve this, we developed a new technique, termed electroporation in situ. Peptides are introduced corresponding to the proteins' points of contact in order to specifically block their interaction. Recent results demonstrated the exquisite ability of this technique to distinguish between closely related signals and open new avenues for the development of peptidomimetic drugs. This apparatus has been used by over a hundred labs worldwide, with results published in Nature, Science, PNAS and other Journals. This work has been an excellent training ground for a number of graduate students. Dr Heather Brownell (Ph.D., 1997) was a runner-up for the NSERC doctoral prize and Dr Adina Vultur (Ph.D., 2005) was the recipient of the Governor General's Academic Gold medal as the top graduating Ph.D. student of Queen’s University. Rozanne Arulanandam (Ph.D. candidate), is on her way to being the next. Several more graduate and 4th year project students had external awards and a large number of publications.

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Mukhopadhyay UK, Cass J, Raptis L, Craig AW, Bourdeau V, Varma S, Gupta SS, Elliott BE, Ferbeyre G. Dataset of STAT5A status in breast cancer. Data Brief. 2016 Mar 4;7:490-2 Utpal K. Mukhopadhyay*, Jamaica Cass*, Leda Raptis, Andrew W. Craig, Véronique Bourdeau, Sonal Varma, Sandip SenGupta, Bruce E. Elliott and Gerardo Ferbeyre. STAT5A is regulated by DNA damage via the tumor suppressor p53. Cytokine, 82:70-79. Mulu Geletu, Stephanie Guy, Samantha Greer and Leda Raptis*. Differential effects of polyoma virus middle tumor antigen mutants upon gap junctional, intercellular communication. Experimental Cell Research, 336:223-231 (2015). Arulanandam R, Batenchuk C, Angarita FA, Ottolino-Perry K, Cousineau S, Mottashed A, Burgess E, Falls TJ, De Silva N, Tsang J, Howe GA, Bourgeois-Daigneault M-C, Conrad DP, Daneshmand M, Breitbach CJ, Kirn DH, Raptis L, Sad S, Atkins H, Huh M, Diallo J-S, Lichty, BD, Ilkow CS, Le Boeuf F, Addison CL, McCart JA and Bell JC. VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection. Cancer Cell, 28:210-24 (2015). Geletu M., Guy S., Firth K. and Raptis L*. (2014). A functional assay for gap junctional examination; electroporation of adherent cells on Indium-Tin oxide. Journal of Visualized experiments, 92:e51710 Assi HH, Paran C, Vanderveen N, Savakus J, Doherty R, Petruzzella E, Hoeschele JD, Appelman H, Raptis L, Mikkelsen T, Lowenstein PR, Castro MG. (2014). Pre-clinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy. Journal of Pharmacology and Experimental Therapeutics. 349:458-469 Guy S, Geletu M, Arulanandam R, Raptis L*. (2014). Stat3 and gap junctions in normal and lung cancer cells. Cancers (Basel), 6:646-62. Geletu M, Guy S, Arulanandam R, Feracci H and Raptis L. (2013). Engaged for survival; from cadherin ligation to Stat3 activation. JAK-STAT, Volume 2, issue 4e27363-1 (8 pages). Geletu, M., Arulanandam, R., Saez, B., Larue, L., Feracci, H. and Raptis, L*. (2013). Classical cadherins control survival through the gp130/Stat3 axis. BBA-Molecular Cell Research, 1833:1947-1959 Geletu M., Guy S. and Raptis L*. (2013). Effects of Src and Stat3 upon intercellular communication in lung cancer lines. Anticancer Research, 33:4401-4410. Carefoot E, Raptis L, Greer P and Elliott BE. (2013). The role of Met, Src and Stat3 in basal-like breast cancer invasion. PMC ID: 3624480. Journal: BMC Proceedings. Publisher: BioMed Central. Geletu, Mulu, Trotman-Grant, Aaron and Raptis, Leda* (2012). Mind the gap: Regulation of gap junctional, intercellular communication by the Src oncogene product and its effectors. Anticancer Research, 32:4245-50. Jamaica Cass, Sonal Varma, Andrew Day, Waheed Sangrar, Ashish Rajput, Leda Raptis, Jeremy Squire, Yolanda Madarnas, Sandip Sengupta, Bruce Elliott*. (2012). Automated quantitative analysis of p53, cyclin D1, Ki67 and pERK expression in breast carcinoma does not differ from expert pathologist scoring and correlates with clinico-pathological characteristics. Cancers (Basel) 4:725-742. Geletu M, Greer S, Arulanandam R, Tomai, E, Trotman-Grant A, and Raptis, L*.(2012).Stat3 is a positive regulator of gap junctional communication in cultured, human lung carcinoma cells. BMC cancer, 2012, 2:605 (13 pages). Raptis, L*, Arulanandam, R., Geletu, M. and Turkson, J. (2011). The R(h)oads to Stat3. Stat3 activation by the Rho GTPases. Experimental Cell Research, 317:1787-95. Geletu, M. and Raptis, L*. (2011). Viral oncogenes and the retinoblastoma family. In: Retinoblastoma, Govindasamy Kumaramanickavel Editor. InTech, Croatia. Open access, Book chapter. Retrieved from http://www.intechweb.org/subject/ Zhou Z, Hao Y, Liu N, Raptis L, Tsao MS, Yang X. (2011). TAZ is a novel oncogene in non-small cell lung cancer. Oncogene, 30:2181-6. Valiyeva F, Jiang F, Elmaadawi A, Moussa M, Yee SP, Raptis L, Izawa JI, Yang BB, Greenberg NM, Wang F, Xuan JW. (2011).Characterization of the oncogenic activity of the novel TRIM59 gene in mouse cancer models. Mol Cancer Therapeutics, 10:1229-40. Arulanandam, R., Geletu, M., Feracci, H. and Raptis, L.* (2010). RacV12 requires gp130 for Stat3 activation, cell proliferation and migration. Experimental Cell Research,316:875-886. Greer S, Honeywell R, Geletu M, Arulanandam R and Raptis L*. (2010). Housekeeping genes; expression levels may change with density of cultured cells. Journal of Immunological Methods,355:76-79. Arulanandam, R, Geletu M and Raptis L*. (2010). The Simian Virus 40 Large Tumor antigen requires Src for full neoplastic transformation. Anticancer Research, 30:47-54. Mukhopadhyay UK, Mooney P, Jia L, Eves R, Raptis L and Mak AS. (2010). Doubles game: Src-Stat3 versus p53-PTEN in cellular migration and invasion. Molecular and Cellular Biology, 30:4980-4995. Papadakis AI, Paraskeva E,Peidis P, Muaddi H,Raptis L, Pantopoulos K, Simos G and Koromilas AE.(2010). The eIF2a kinase PKR is implicated in the hypoxic response by acting as a transcriptional suppressor of the HIF1A gene. Cancer Research, 70:7820-7829. Raptis, L*, Arulanandam, R., Vultur, A., Geletu, M., Chevalier, S. and Feracci, H. (2009). Beyond structure, to survival: activation of Stat3 by cadherin engagement. Biochemistry and Cell Biology, 87:835-43. Mohan R, Arulanandam R, Vultur A, Lo O, Cao J and Raptis L*. (2009). Differential effects of Adenovirus E1A and Simian Virus 40 Large Tumor antigen upon Erk and Akt activity levels in rodent fibroblasts. Trends in Cell and Molecular Biology, 3:59-68.