Faculty: Leonardo Salmena, PhD
General Research Areas: Biochemical & Molecular Pharmacology; Second Messengers & Signal Transduction.
Competitive Endogenous RNA, Phosphoinositide Signaling and Chemotherapy Resistance in Leukemia.
Our ongoing scientific interests include investigations of signaling perturbations in the oncogenic PI3-kinase pathway, specifically the function and aberrations of the tumor suppressor PTEN in the context of leukemogenesis. We are currently investigating post-translational mechanisms of PTEN regulation and control of PTEN expression by microRNA.
We have recently identified a novel post-transcriptional mechanism of gene regulation of PTEN mediated through competitive interaction of cellular RNA molecules. These finding have opened a new field of study which embraces the notion that all cellular RNA molecules (coding and non-coding) have the ability to compete for microRNA binding and thereby mediate their relative functions, in trans. Future studies include functional analyses of the non-coding transcriptome, its aberrant regulation, and the consequences for human disease and cancer therapy.
Finally, working closely with the Leukemia group at the Princess Margaret Cancer Centre, we are intensely investigating the genetic alterations and molecular mechanisms that underlie the pathogenesis of human leukemias, with the aim of identifying cellular mechanisms of chemotherapy resistance, new therapeutic targets and novel strategies for disease prevention.
Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumor suppressor. Nat Rev Mol Cell Biol. 2012; 13(5):283-96.
Narod SA, Salmena L. BRCA1 and BRCA2 mutations and breast cancer. Discovery Med. 2011; 12:445-53.
Tay Y, Kats L, Salmena L, Weiss D, Tan SM, Ala U, Karreth F, Poliseno L, Provero P, Di Cunto F, Lieberman F, Rigoutsos I, Pandolfi PP. Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs. Cell, 2011; 147: 344–357.
Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. The ceRNA hypothesis: the Rosetta stone of a hidden microRNA-dependent language. Cell, 2011; 146:353-358.
Poliseno L*, Salmena L*, Zhang, J, Carver, B, Haveman, W.J, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology.Nature, 2010; 465:1033-8. * shared first authorship
Alimonti A, Carracedo A, Clohessy JG, Trotman LC, Nardella C, Egia A, Salmena L, Sampieri K, Haveman WJ, Brogi E, Richardson A.L, Zhang, J, Pandolfi PP. Subtle variations in Pten dose determine cancer susceptibility. Nat Gen. 2010; 42:454-8.
Poliseno L, Salmena L, Riccardi, L, Fornari, A, Song, M.S, Hobbs, R.M, Sportoletti, P, Varmeh, S, Egia, A, Fedele, G, Rameh, L, Loda, M, Pandolfi PP. Identification of the miR-106b~25 microRNA Cluster as a Proto-Oncogenic PTEN-Targeting Intron that Cooperates with its Host Gene MCM7 in Transformation. Sci Signal. 2010; 3(117):ra29.
Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC. Evidence that Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor that Inhibits PI3K Signaling. Cancer Cell, 2009; 16:115-25.
Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature, 2008; 455:813-7.
Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008; 118:3065-74.
Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN tumor suppression. Cell, 2008; 133:403-14.
Salmena L, Pandolfi PP. Changing venues for tumour suppression: balancing destruction and localization by monoubiquitylation. Nat Rev Cancer, 2007; 7:409-13./p>
Salmena L, Hakem R. Caspase-8 Deficiency in T-Cells Leads to a Lethal Lymphoinfiltrative Immune Disorder. J Exp Med. 2005; 202:727-32.
Su H, Bidère N, Zheng L, Cubre A, Sakai K, Dale J, Salmena L, Hakem R, Straus S, Lenardo M. Requirement for caspase-8 in NF-kappaB activation by antigen receptor. Science, 307:1465-8.
Salmena L, Lemmers B, Hakem A, Matysiak-Zablocki E, Murakami K, Au PY, Berry DM, Tamblyn L, Shehabeldin A, Migon E, Wakeham A, Bouchard D, Yeh WC, McGlade JC, Ohashi PS, Hakem R. Essential role for caspase-8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev. 2003; 17:883-95.
Department of Pharmacology & Toxicology
1 King's College Circle
Telephone: 416-978-3341/416-946-4501 X3695
OCI website: http://www.uhnres.utoronto.ca/researchers/profile.php?lookup=57165
Lab website: www.salmenalab.com