Seminar Series: Fall 2016 ~~ Friday, September 23, 2016 2:00-3:00 PM ...
T. M. Ruenger, MD PhD
Thomas M. Ruenger (Rünger), MD PhD (equiv.)
Professor and Vice-Chair of Dermatology
Professor of Pathology and Laboratory Medicine
Department of Dermatology, Boston University School of Medicine
Education and Training:
Medical Schools, University of Ulm and University of Kiel, Germany
Postdoctoral Fellowship, Laboratory of Molecular Carcinogenesis, NCI, NIH
Dermatology and Allergology Residency, University of Würzburg, Germany
- photosensitive skin diseases
- Repair of UV-induced DNA damage
- UV-induced DNA damage signaling
- UV-induced DNA damage responses
- Biology of the extracellular matrix
Area of interest 1:
Exposure of the skin to sunlight is a major contributor to the pathogenesis of various different skin diseases, including skin cancer. Part of my research is aimed at further characterizing the effects of ultraviolet light on skin cells, and involves investigations on DNA damage signaling, cell cycling, apoptosis, DNA repair (including nucleotide excision repair, translesional DNA synthesis, and DNA recombination), and mutagenesis. A particular interest is to dissect effects of different wavelengths of the solar UV-spectrum (shortwave UVB vs. longwave UVA).
With detailed DNA sequence analysis of UVA- and UVB-induced mutations, we recently reported that UVA induces mainly mutations that are typical for pyrimidine dimer-type of DNA damage, just like UVB, and only very few mutations typical of oxidative DNA damage. We hypothesize that a weaker DNA damage response to UVA, as compared to UVB, profoundly changes the outcome of UVA- and UVB-induced DNA damage, making it much more likely that a UVA-induced DNA lesion causes mutation formation, and that a UVB-induced mutation is more likely repaired correctly and thereby less likely to cause mutation formation. We have studied activation of cell cycle checkpoints, DNA repair efficiency, and apoptosis and found a profound difference between UVA- and UVB-induced responses mainly in the way how cells activate cell cycle checkpoints. We have identified several DNA damage response proteins (including cell cycle regulators) that are differentially activated by UVB and UVA, including ATM, Chk1, p53, p21, XPCC, FANCD2 and others. These provide the molecular markers of different DNA damage responses to UVA and UVB, as shown functionally and by the different mutation formation outcome. These data provide good further evidence that longwave ultraviolet light (UVA) cannot be regarded safe, and that exposure to pure UVA, as e.g. in tanning studios, is dangerous.
Area of interest 2:
The observation of morphea (= circumscript scleroderma) in several patients that were treated with a cathepsin K inhibitor in an osteoporosis clinical trial raised my interest in a putative role of cathepsin K in skin biology. This protease has so far has only been known as the main bone-degrading protease in osteoclasts where its collagenolytic properties mediate bone degradation. We reported that it is not expressed in normal skin but in scars, and suggested a role of cathepsin K in maintaining the homeostasis of the cutaneous extracellular matrix. We also found it to be strongly expressed in melanomas and that its inhibition reduced melanoma cell invasion. These data suggest an important role of cathepsin K in melanoma invasion and metastasis. Cathepsin K was also found to be induced by ultraviolet light in dermal fibroblasts (in-vivo and in-vitro). As it is the strongest elastase in humans, it may play in major role in photoaging of skin, which is characterized by a massive degradation of dermal elastic fibers.
While degradation of collagen and other extracellular matrix proteins has been widely studied in skin and other diseases, most of this research has focused on protein degradation by metalloproteinases in the extracellular space. Cathepsin K is a lysosomal protein with a very low ph optimum of 5.5. This suggests that it contributes to extracellular matrix degradation by degrading internalized extracellular matrix proteins after endocytosis. And indeed, we have been able to demonstrate internalization of extracellular collagen and elastin into lysosomes by endocytosis and a cathepsin K dependent degradation of these proteins in lysosomes. This demonstration of intracellular, as opposed to intracellular matrix degradation opens a whole new avenue to study processes of fibrosis, angiogenesis, tumor invasion and metastasis. We have also characterized signals of cathepsin K regulation and found it upregulated by IL-1 and cellular confluence, and downregulated by TGF-beta. Further characterization of receptor-mediated endocytosis of collagen is currently pursued.
- Rünger TM and Kappes UP (2008) Mechanisms of mutation formation with long-wave ultraviolet light (UVA). Photodermatology, Photoimmunology, Photomedicine 24, 2-10
- Quintanilla-Dieck MJ, Keady M, Bhawan J, Rünger TM (2008) Role of cathepsin K in melanoma invasion. Journal of Investigative Dermatology, 128, 2281 – 2288
- Rünger TM (2007) How different wavelengths of the ultraviolet spectrum contribute to skin carcinogenesis – role of the cellular damage response. Journal of Investigative Dermatology 127, 2103-5
- Rünger TM, Quintanilla-Dieck MJ, Bhawan J (2007) Role of cathepsin K in the turnover of the dermal extracellular matrix during scar formation. Journal of Investigative Dermatology 127, 293 – 297
- Dunn J, Potter M, Rees A, Rünger TM (2006) Activation of the Fanconi anemia/BRCA pathway and recombination repair in the cellular response to solar ultraviolet light. Cancer Research 66, 11140 – 11147
- Kappes UP, Luo D, Potter M, Schulmeister K, Rünger TM (2006) Short- and long-wave ultraviolet light (UVB and UVA) induce similar mutations in human skin cells. Journal of Investigative Dermatology 126, 667 – 675
- Rünger TM, Vergilis I, Sarkar-Agrawal P, DePinho RA, Sharpless NE (2005) How disruption of cell cycle regulating genes might predispose to sun-induced skin cancer. Cell Cycle 4, 643 – 645
- Sarkar P, Vergilis I, Sharpless NE, DePinho R, Rünger TM (2004) Loss of p16INK4a or p19ARF confers deficient repair of DNA photoproducts. Journal of the National Cancer Institute 96, 1790 – 179