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Oncogenomics: Reuven Agami

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Reuven Agami Ph.D professorGroup leader, Head of Division

About Reuven Agami

Controlling cancer by RNA

Over the past years our main research objective was to understand the cancerous process in humans and identify essential cancerous genes and pathways. This is with the assumption that the knowledge obtained on these genes will allow us to design novel cancer therapeutic approaches. We developed an RNA interference (RNAi) approach to inactivate genes in mammalian cells and used it to identify potential novel human tumor suppressors (e.g. PITX1, BRD7, and RBM38) and to characterize in detail their mechanism of action and their role in cancer. Additionally, we initiated several genome-wide approaches to identify cancer causing microRNAs, an emerging gene family encoding for endogenous small non-coding RNAs. With these tools we discovered and characterized the role of the miR-372 family in tumor initiation and metastasis, and the oncogenic role of miR-221&222 and miR-135 in various types of cancers.

Very recently, we used expression and knockdown libraries of RNA binding proteins (RBPs) to search for those that regulate microRNA activity. We uncovered the existence of interplay between RBPs and microRNAs and described its impact on cellular differentiation, cell proliferation, and stress. Additionally, we generated unique genetic tools to study Alternative cleavage and polyadenylation of mRNAs (APA). With these tools we characterized the role of the gene PABPN1 as a suppressor of APA, and linked for the first time APA with a genetic disease caused by mutations in PABPN1. We further expanded this research line and now connect APA with cancer and study how APA affects protein translation and cellular behavior.

Last, we explore novel p53 functions. p53 is a prototype tumor suppressor gene mutated in more than half of human tumours. Our activities unravelled the binding of p53 to conserved genomic regions that possess all known hallmarks of enhancers of transcription. We show that p53 induces a unique type of non-protein coding RNAs (called enhancer-RNAs) from these loci to control the expression of distal genes. Moreover, we explore on a transcriptome scale the effect of p53 activation on protein translation. We propose that p53 activate a bimodal tumor-suppressive regulatory program in which proliferation arrest is imposed mainly at the transcriptional level, whereas cell growth is inhibited by global repression of the translation machinery through inhibition of the mTOR pathway. We now explore the tools we constructed in characterizing cancer metastasis and utilize our findings for cancer therapy.

 

Co-workers

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Ruiqi Han

PhD student

Experience

After graduation from master oncology of Vrije Universiteit Amsterdam, I immediately joined the group of Reuven Agami for my Phd study. I am involved in projects on the role of promoters in regulating translational efficiency. By studying this mechanism, it would be possible to understand the gene regulation network better and deeper.

 

 

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Gözde Korkmaz

Postdoctoral fellow

Experience

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Li Li

PhD student

Personal details

Groups

Experience

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Fabricio Loayza Puch

Postdoctoral fellow

Experience

I study global modulation of protein translation during oncogenic stress and cellular transformation. Using ribosome profiling and next generation sequencnig, I am able to study genome-wide protein translation with nucleotide resolution. I also focus on the effect of RNA-binding proteins on protein translation during metastasis and invasion.

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Rui Lopes

PhD Student

Experience

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Alejandro Pineiro Ugalde

Postdoctoral fellow

Experience

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Behzad Moumbeini

PhD student

Experience

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Sun, J

Jianhui (Jane) Sun

PhD student

Experience

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Research updates View All Updates

  • ERC-advanced project on enhancer RNAs

    2013:  Awarded an ERC-advanced project on enhancer RNAs

  • Awarded a KWF grant

    2013: Awarded a KWF grant to study protein translation in acquired resistance to cancer therapy.

Key publications View All Publications

  • eRNAs are required for p53-dependent enhancer activity and gene transcription

    Mol Cell. 2013; 49: 524-35

    Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, Elkon R, Melo SA, Léveillé N, Kalluri R, de Laat W, Agami et al.

    Link to PubMed
  • The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites

    Cell. 2012; 149: 538-53

    Jenal M, Elkon R, Loayza-Puch F, van Haaften G, Kühn U, Menzies FM, OudeVrielink JA, Bos AJ, Drost J, Rooijers K, Rubinsztein DC, Agami et al.

    Link to PubMed
 
 

Recent publications View All Publications

  • Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9

    Nature Biotechnology 2016, Jan 11. doi: 10.1038/nbt.3450

    Korkmaz G, Lopes R, Ugalde AP, Nevedomskaya E, Myacheva K, Zwart W, Agami R.

    link to PubMed
  • Myc coordinates transcription and translation to enhance transformation and suppress invasiveness

    EMBO Reports 2015, 16(12):1723-36. doi: 10.15252/embr.201540717. Epub 2015 Nov 4

    Elkon R, Loayza-Puch F, Korkmaz G, Lopes R, Van Breugel PC, Bleijerveld OB, Altelaar AM,Wolf E, Lorenzin F, Eilers M, Agami R.

    link to PubMed
 

Contact

  • E-mail

    a.laan@nki.nl

  • Telephone Number

    +31 20 512 2015

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