Head


Cornelis Calkhoven
Cornelis Calkhoven

Postdocs

Christine Müller

Laura Zidek

PhD Students

Tobias Ackermann

Mohamad Amr Zaini

Götz Hartleben

Kyungmin In

Technicians

Sabrina Eichwald

Guests

Verena Gräfe (apprentice)



 

Calkhoven Laboratory

Eukaryotic gene regulation

 

Post-transcriptional gene regulation in ageing - metabolism - cancer

Ageing, metabolic disorders and cancer share similar underlying molecular mechanisms. Our aim is to understand the impact of post-transcriptional gene regulation on these phenomena. In particular, we study how the mTORC1 (mammalian target of rapamycin complex 1) signalling network controls mRNA-translation in response to altered nutrient and/or energy availability. C/EBPα and -β transcription factors are key-regulators in metabolism, innate immunity and senescence. We discovered a cis-regulatory mRNA element (uORF) in the C/EBPα and -β mRNAs that permits translational regulation of these mRNAs through the mTORC1 pathway. Our current research focuses on the role of mTORC1-C/EBP regulation in determining metabolic health and lifespan. In addition, we examine how deregulation of and/or mutations in C/EBPα and -β protein isoforms contribute to cancer development. Another interest of the lab is to understand transcription factor-microRNA regulatory networks that mediate tumour suppressive and oncogenic functions of C/EBP and Myc proteins. Their relevance for cancer cell metabolism (the Warburg effect) and stem cell ageing is currently under investigation. Finally, we develop Translational-Control-Reporter-Systems with the aim to ‘translate’ our research into clinical-pharmacological applications.

 

Projects

maus2

maus3
  • Regulation of C/EBPα and -β mRNA translation in the development of metabolic syndrome and cancer.

  • Determination of health and lifespan by the mTORC1-C/EBPβ pathway.

  • Control of cancer cell and stem cell metabolism by C/EBPs and c-Myc.

  • Identification of tumor-suppressive and oncogenic microRNAs that are under control of C/EBPs or c-Myc.

  • Function of C/EBPα in the control of rDNA transcription during leukaemia development.

  • Translational-Control-Reporter-Systems for the search of caloric restriction mimetics and anti-cancer compounds.

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    Recent selected publications

    • Dey S, Savant S, Teske BF, Hatzoglou M, Calkhoven CF, Wek RC (2012) Transcriptional repression of ATF4 by C/EBPß differentially regulates the integrated stress response. J Biol Chem, May 3, 2012, doi: 10.1074/jbc.M112.351783. [Journal]
    • Mielke N, Schwarzer R, Calkhoven CF, Kaufman R, Dorken B, Leutz A, Jundt F (2011) Eukaryotic initiation factor 2α phosphorylation is required for B cell maturation and function in mice. Haematologica, 96, 1261-1268. [PubMed]
    • Luther J, Driessler F, Megges M, Hess A, Herbort B, Mandic V, Zaiss MM, Reichardt A, Zech C, Tuckermann JP, Calkhoven CF, Wagner EF, Schett G and David J-P (2011) Elevated Fra-1 expression causes severe lipodystrophy. J Cell Sci, 124, 1465-1476. [PubMed]
    • Juenemann K, Weisse C, Reichmann D, Kaether C, Calkhoven CF, Schilling G (2010) Modulation of mutant Huntingtin N-terminal cleavage and its effect on aggregation and cell death. Neurotox Res, 20, 120-133. [PubMed]
    • Müller C, Calkhoven CF (2010) C/EBPα enters the nucleolus. Cell Cycle, 9, 1229-1230. [PubMed]
    • Müller C, Bremer A, Schreiber S, Eichwald S and Calkhoven CF (2010) Nucleolar retention of a translational C/EBPα isoform stimulates rDNA transcription and cell size. EMBO J, 29, 897-909. [PubMed]
    • Wethmar K, Bégay V, Smink JJ, Zaragoza K, Wiesenthal V, Dörken B, Calkhoven CF and Leutz A (2010) C/EBPβΔuORF mice - a genetic model for uORF-mediated translational control in mammals. Genes Dev, 24, 15-20. [PubMed]
    • van Gorp AGM, van der Vos KE, Brenkman AB, Bremer A, van den Broek N, Zwartkruis F, Hershey JW, Burgering BMT, Calkhoven CF and Coffer PJ (2009) AGC kinases regulate phosphorylation and activation of eukaryotic translation initiation factor 4B. Oncogene, 28, 95-106. [PubMed]
    • Wiesenthal V, Leutz A, Calkhoven CF (2006) A translation control reporter system (TCRS) for the analysis of translationally controlled processes in the vertebrate cell. Nucleic Acids Res, 34, e23. [PubMed]
    • Wiesenthal V, Leutz A, Calkhoven CF (2006) Analysis of translation initiation using a translation control reporter system (TCRS). Nat Protoc, 1, 1531-1537. [PubMed]
    • Jundt F, Raetzel N, Müller C, Calkhoven CF, Kley K, Mathas S, Lietz A, Leutz A, Dörken B (2005) A rapamycin derivative (everolimus) controls proliferation through down-regulation of truncated CCAAT enhancer binding protein β and NF-κB activity in Hodgkin and anaplastic large cell lymphomas. Blood, 106, 1801-1807. [PubMed]
    • Müller C, Calkhoven CF, Sha X, Leutz A (2004) The CCAAT enhancer-binding protein α (C/EBPα) requires a SWI/SNF complex for proliferation arrest. J Biol Chem, 279, 7353-7358. [PubMed]
    • Calkhoven CF§, Müller C§, Martin R, Krosl G, Pietsch H, Hoang T, Leutz A (2003) Translational control of SCL isoform expression in hematopoietic lineage choice. Genes Dev, 17, 959-964. [PubMed] § shared first author
    • Calkhoven CF*, Müller C, Leutz A (2002) Translational control of gene expression and disease. Trends Mol Med, 8, 577-583. [PubMed] * corresponding author
    • Calkhoven CF*, Müller C, Leutz A* (2000) Translational control of C/EBPα and C/EBPβ isoform expression. Genes Dev, 14, 1920-1932. [PubMed] * corresponding author

     

    Last update: May 23, 2012
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