Haarmann-Stemmann research group: AhR and UVB signaling

Head of research group:
Dr. rer. nat. Thomas Haarmann-Stemmann tl_files/bilder/mail.gif
Phone: +49 (0)211-3389-204

Postdoc:
Dr. rer. nat. Melina Mescher tl_files/bilder/mail.gif

PhD students
:
Katharina Rolfes, MSc tl_files/bilder/mail.gif
Marius Pollet, MSc tl_files/bilder/mail.gif

Master student:

Stephan Moosmann tl_files/bilder/mail.gif

Technical Assistance:

Ragnhild Wirth, BTA tl_files/bilder/mail.gif

Research profile

The research group „AhR and UVB signaling“ concentrates on the molecular and cell biological characterization of the aryl hydrocarbon receptor (AhR) signaling pathway. The main focus of the research is to elucidate new functions of the AhR in keratinocytes exposed to ultraviolet radiation (UV) or polycyclic aromatic hydrocarbons (PAK). The overall aim is to develop new strategies for the prevention of environmentally induced skin diseases. For the first time, the working group was able to identify an anti-apoptotic function of the AhR signaling pathway in human and murine keratinocytes and mice skin exposed to UV irradiation. This function contributes to the accumulation of damaged cells that can finally result in the development of skin cancer and premature skin aging. Furthermore, the working group contributed to the finding that the AhR is an important regulator for collagen degrading matrix metalloprotease 1 in keratinocytes and fibroblasts cultivated under UV or PAK exposure as well as human skin. Thereby, the AhR contributes to extrinsic skin aging. Another contribution regards the development of a novel AhR-inhibitor which is approved as ingredient for cosmetics for topical application and protects against UV-induced signal transduction. One other aspect of the working group’ research is the investigation of the regulation and function of the AhR-repressor, a putative feedback-inhibitor of the AhR signaling cascade, particularly in dermal fibroblasts. Currently, the research group investigates to what extent the AhR is involved in (i) NF-κB-mediated as well as (ii) DNA-damage-dependent (cell cycle arrest, apoptosis, DNA-repair) stress responses and the consequences for the development of UV-induced cutaneous squamous cell carcinoma in the skin.

Projects

The project "Interaction of AhR and NF-κB-dependent signaling pathways for the development of cutaneous squamous cell carcinoma" aims to elucidate the molecular interaction of AHR and NF-κB in UVB-irradiated keratinocytes, and to characterize the functional relevance of this cross-talk for the development of cutaneous squamous cell carcinoma and its precursors in an appropriate mouse model. Based on own preliminary work, we will test the hypothesis that the activity of one signaling pathway can be modulated by inhibiting the other, which may present a promising strategy for the prevention of UVB-induced skin carcinogenesis. The research project is conducted in cooperation with the research groups Krutmann and Esser. The project is funded by the Wilhelm Sander Foundation.

The scope of the project "AHR as regulator of DNA damage-dependent response" is to characterize the importance of the AhR signaling cascade for cancer- and aging-associated processes, such as cell-cycle arrest, DNA repair, and apoptosis, in UVB-exposed keratinocytes, cutaneous squamous cell carcinoma cells, and murine skin. Preliminary data from our group indicate that AhR-dependent signaling pathways can regulate the cell-cycle of keratinocytes and thereby influence the initiation of nucleotide excision repair (NER) and apoptosis upon UVB-induced DNA damage. Interestingly, AhR seems to repress both NER and apoptosis and thus significantly contributes to the initiation and promotion of UVB-induced squamous cell carcinomas and photoaging. The aim of the study is to identify novel AhR-dependent signaling processes, which can be addressed for the prevention and / or therapy of environmentally-induced skin malignancies and premature skin aging. The project is performed in cooperation with the research group Krutmann and has been supported by the Jürgen Manchot Foundation, further funding is currently applied for.

Cooperations

IUF internal:
Krutmann research group
Esser research group
Haendeler research group
Fritsche research group
Ventura liaison research group
Weighardt liaison research group

International:
Prof. Christoph F. Vogel, University of California Davis, CA, USA
Prof. Thierry Douki, CEA Grenoble, France

Selected publications

Tigges J*, Haarmann-Stemmann T*, Vogel CF, Grindel A, Hübenthal U, Brenden H, Grether-Beck S, Vielhaber G, Johncock W, Krutmann J*, Fritsche E*: The new aryl hydrocarbon receptor antagonist E/Z-2-benzylindene-5,6-dimethoxy-3,3-dimethylindan-1-one protects against UVB-induced signal transduction. Journal of Investigative Dermatology 134(2): 556-559, 2014. (* equal contribution) [pubmed] (open access)

Vogel CF, Kahn EM, Leung P, Gershwin ME, Chang WLW, Wu D, Haarmann-Stemmann T, Hoffmann A, Denison MS: Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-κB. Journal of Biological Chemistry 289(3): 1866-1875, 2014. [pubmed] (open access)

Frauenstein K, Sydlik U, Tigges J, Majora M, Wiek C, Hanenberg H, Abel J, Esser C, Fritsche E, Krutmann J*, Haarmann-Stemmann T*: Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1. Cell Death and Differentiation 20(10): 1425-1434, 2013. (* equal contribution) [pubmed] (open access)