Professor of Therapeutic Radiology and Genetics

* B.S. University of Illinois, 1973
* Ph.D. Ohio State University, 1979

Research Interests:

* Ultraviolet Light and Skin Cancer

Honors:      

* Argall and Anna Hull Award
* Swebelius Award
* Arnold Rikli Prize for Photobiology
* Finsen Lecture
* American Skin Association Achievement Award for Research in Skin Cancer/Melanoma

Cancer begins as an encounter between a carcinogen and a gene. Our lab is pinpointing these early events, which occur decades before tumors appear. Using sunlight-induced human skin cancer as an experimental system, we seek to identify gene targets for sunlight and learn how loss of their functions -- such as UV-induced apoptosis -- leads to the onset of cancer in normal-appearing skin.
       

Current Research:   

       
   
The story thus far, from photons up to cells: UV leads to mutations at the site of DNA photoproducts (rather than elevating genomic instability); the important photoproducts are cyclobutane dimers and (6-4) photoproducts, which join adjacent cytosines or thymines; only the cytosine mutates; these unique properties create a characteristic "mutation signature" for UV that can be seen in tumors decades later; sunlight mutates the P53 and PTCH genes in non-melanoma skin cancer; P53 is required for UV-induced apoptosis, which prevents mutations; apoptosis is signaled by DNA photoproducts in actively transcribed genes; and our sun-exposed skin carries about 60,000 tiny clones of P53-mutant keratinocytes. Expansion of single mutant cells into clones is due to physiology rather than a 2nd mutation: UV-induced apoptosis deletes normal stem cell compartments and spares the mutant ones. One cause of apoptosis is exposure of melanin to sunlight, particularly the melanin found in blonde and red hair.
       
   
Now, the lab is in the midst of some "functional genomics" questions:

1. How does a single mutant keratinocyte expand into a clone? To track the clonal expansion of mutant stem cells in a living mouse, and to test the role of cell-cell communication, we are constructing a mouse in which mutant P53 fluoresces. We are also building an in vivo confocal microscope capable of imaging into living skin.
       
   
2. What are the UV targets that trigger apoptosis? In addition to actively-transcribed genes, specific DNA regions such as telomeres and microRNA binding sites are predicted to be UV sensitive. Membrane receptor kinases have also been proposed to be the target. To resolve these questions, we have built a UV microbeam that can irradiate selected cell compartments; we then examine spatially localized signal transduction.
       
   
3. Another way to identify the UV targets is by studying DNA repair in specific gene regions. We've developed a method to measure UV photoproducts and repair in specific genomic regions such as telomeres. The proteins regulating repair can then be identified by RNAi.
       
   
4. What other genes are involved in UV-induced apoptosis? We find that P53 and E2f1 are a regulatory apparatus for an underlying apoptosis pathway that not only initiates the UV response but also appears to prevent birth defects and tumors.
       
 
Clone of p53-mutated keratinocytes in normal human skin. In ordinary individuals (that's you), sun-exposed skin contains up to 40 such clones per square centimeter. Three-dimensionally reconstructed confocal image of an immunostained epidermal whole mount; the apex of the clone lies at the basal layer of the depidermis.