Douglas E. Brash

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

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 TP53 and PTCH genes in non-melanoma skin cancer; TP53 is required for UV-induced apoptosis, which prevents mutations; and our sun-exposed skin carries about 60,000 tiny clones of TP53-mutant keratinocytes.

Now, the lab is in the midst of some 'functional genomics' questions:

1. Was it TP53's role in apoptosis or cell cycle arrest that contributed to the tumor? The phenotype of each skin tumor's TP53 mutation constitutes a "phenotypic signature" that may reveal the answer decades after the event.

2. What are the other genes involved in UV-induced apoptosis? So far, there seem to be two pathways, with different requirements for genes like ARF and BAX. Apoptosis is signaled by UV photoproducts in actively transcribed genes.

3. How does a single mutant cell expand into a clone? Our model is that apoptosis of stem cells after UV allows an adjacent TP53-mutant cell to encroach into the vacated stem cell compartments. We find that TP53-mutant cells expand by colonization, rather than by continuous invasion: clones come in multiples of 12 cells, the size of a morphological stem cell compartment.

4. We find that redox-altering antioxidants upregulate TP53 protein, thereby inducing apoptosis in transformed cells but not normal ones; this specificity suggests a potentially useful cancer prevention strategy. TP53 seems to be detecting alterations in the p16-RB-E2F1-MYC axis, but how?

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.

Representative Publications:

Jonason, A. S., Kunala, S., Price, G. J., Restifo, R. J., Spinelli, H. M., Persing, J. A., Leffell, D. J., Tarone, R. E., and Brash, D. E. Frequent clones of p53-mutated keratinocytes in normal human skin. Proc. Natl. Acad. Sci. USA 93:14025-14029, 1996.

Brash, D. E. Sunlight and the onset of skin cancer. Trends Genet. 13:410-414, 1997.

Brash, D. E. and Pontén J. Skin precancer. Cancer Surv. 32:69-113, 1998.

Brash DE, Wikonkal NM, Remenyik E, van Der Horst GT, Friedberg EC, Cheo DL, van Steeg H, Westerman A, van Kranen HJ. The DNA Damage Signal for Mdm2 Regulation, Trp53 Induction, and Sunburn Cell Formation In Vivo Originates from Actively Transcribed Genes. J Invest. Dermatol. 117:1234-1240, 2001.

Zhang W, Remenyik E, Zelterman D, Brash DE, Wikonkal NM. Escaping the stem cell compartment: Sustained UVB exposure allows p53-mutant keratinocytes to colonize adjacent epidermal proliferating units without incurring additional mutations. Proc. Natl. Acad. Sci. USA 98:13948-13953, 2001.

Havre, PA, O'Reilly, S, McCormick, JJ, and Brash, DE. Transformed and tumor derived human cells exhibit preferential sensitivity to the thiol antioxidants, N-acetyl cysteine and penicillamine. Cancer Res., 62:1443-1449, 2002.

<douglas.brash@yale.edu>

Updated 2 May 2002