Ola Larsson's Group

Post-transcriptional regulation acts after transcription but before synthesis of the protein in processes including mRNA splicing, mRNA transport from the nucleus to the cytoplasm, mRNA stability and mRNA translation. Control of translation is the last step where synthesis of proteins from an mRNA can be avoided or stimulated thus offering a mechanism for fast responses to external stimuli and control of genes whose potentially detrimental expression calls for tight regulation (e.g. oncogenes). In most cases translational control is a process that regulates how many ribosomes that are initiated on each mRNA and differential translation initiation involves a shift in the number of ribosomes synthesizing proteins from each mRNA per time unit and thereby affects the protein level. Translational control can be a general process where the translational activity of most mRNAs is regulated similarly or a specific process only targeting single or groups of mRNAs. The specificity for regulation resides within the mRNA sequence; regions designated RNA-elements often found in the UTRs. Regulation is mediated through interactions between RNA-elements and binding proteins. Specific translational control has been studied in many processes including development, differentiation, hypoxia, response to growth factors, metastasis, irradiation, apoptosis, proliferation and heat shock. However, a synthesis regarding which mRNAs are targeted by what mechanisms and to mediate which biological functions is lacking.

Dysregulation of translational control of gene expression is essential for the malignant phenotype in mammary epithelial cells and out of the approximately 300 cancer-related genes recognized more than three quarters affect translational regulation. Further, the translation factor that has commonly been studied in cancer, initiation factor 4E (eIF4E), is a marker for poor prognosis breast cancer and even among poor prognosis triple negative breast cancers high eIF4E is a risk factor. However, the mechanisms and the results of dysregulated translational control in breast cancer with regard to initiation, progression, metastasis and prognosis are largely unknown. To understand the role of translational control in breast cancer, more knowledge of how translational control is organized at a genome wide level is essential.

The goal of our research program is to generate knowledge about the organization, specificity and mechanisms of translational control. Such information will pave the way towards studies of how translational control can integrate diverse signals that affect breast cancer prognosis; used to identify molecular subtypes driven by translation; and used to identify molecular mechanisms that are potential targets for treatment. From the perspective of treatment of breast cancer, finding genes and mechanisms that define dysregulation of translational control may guide us towards new therapeutic targets for treatment of poor prognosis breast cancers.

Funding

• Swedish Research Council (VR)
• Swedish Cancer Society
• Cancer Society in Stockholm
• Karolinska Institutet Funds
• STRATCAN
• Knut and Alice Wallenberg Foundation

Developed softwares

1. "RECIT", a tool for integration and selection of biologically active putative RNA-elements.
2. "anota" for analysis of differential translation.
3. "bTransform" for transformation of replicated data.

Group members

Ola Larsson, Assistant Professor, Group leader
Laia Masvidal-Sanz, Post-doctoral fellow
Vincent van Hoef, Post-doctoral fellow
Johannes Ristau, Graduate student
Christian Oertlin, PhD

Alumni

Julie Lorent, Graduate student
Shuo Liang, Graduate student
Eva Bjur, Post-doctoral fellow
Matthew Parker, Post-doctoral fellow (visiting)
Carl Murie, Post-doctoral fellow
Elveda Caliskan, Master student

Selected publications

Fibrotic extracellular matrix activates a profibrotic positive feedback loop.
Parker M, Rossi D, Peterson M, Smith K, Sikström K, White E, et al
J. Clin. Invest. 2014 Apr;124(4):1622-35

Correlation of regional emphysema and lung cancer: a lung tissue research consortium-based study.
Hohberger L, Schroeder D, Bartholmai B, Yang P, Wendt C, Bitterman P, et al
J Thorac Oncol 2014 May;9(5):639-45

mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation.
Morita M, Gravel S, Chénard V, Sikström K, Zheng L, Alain T, et al
Cell Metab. 2013 Nov;18(5):698-711

Re-analysis of genome wide data on mammalian microRNA-mediated suppression of gene expression.
Larsson O, Nadon R
Translation (Austin) 2013 ;1(1):e24557

Distinct translational control in CD4+ T cell subsets.
Bjur E, Larsson O, Yurchenko E, Zheng L, Gandin V, Topisirovic I, et al
PLoS Genet. 2013 May;9(5):e1003494

Distinct perturbation of the translatome by the antidiabetic drug metformin.
Larsson O, Morita M, Topisirovic I, Alain T, Blouin M, Pollak M, et al
Proc. Natl. Acad. Sci. U.S.A. 2012 Jun;109(23):8977-82

anota: Analysis of differential translation in genome-wide studies.
Larsson O, Sonenberg N, Nadon R
Bioinformatics 2011 May;27(10):1440-1

Identification of differential translation in genome wide studies.
Larsson O, Sonenberg N, Nadon R
Proc. Natl. Acad. Sci. U.S.A. 2010 Dec;107(50):21487-92

eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression.
Furic L, Rong L, Larsson O, Koumakpayi I, Yoshida K, Brueschke A, et al
Proc. Natl. Acad. Sci. U.S.A. 2010 Aug;107(32):14134-9

mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs.
Dowling R, Topisirovic I, Alain T, Bidinosti M, Fonseca B, Petroulakis E, et al
Science 2010 May;328(5982):1172-6