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Douglas E. Brash |
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| Professor of Therapeutic Radiology and Genetics |
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* B.S. University of Illinois, 1973
* Ph.D. Ohio State University, 1979
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| Research Interests: | |
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| * Ultraviolet Light and Skin Cancer
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| Honors: | |
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* 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
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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.
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| Current Research: | |
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| 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.
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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.
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| 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.
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| 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.
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| 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.
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| 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. |
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| Representative Publications: | |
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Knezevic, D, Zhang, W, Rochette, P and Brash, DE. Bcl-2 is the target
of a UV-inducible apoptosis switch and a node for UV signaling. Proc.
Natl. Acad. Sci. USA. 104:11286-91, 2007.
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| Zhang, W, Hanks, AN, Florell, SR, Allen, SM, Alexander, A Boucher, K,
Brash*, DE, and Grossman*, D. UV-induced apoptosis drives clonal
expansion during skin tumor development. Carcinogenesis, 26:249-257,
2005. * co-senior authors
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Takeuchi, S, Zhang, W, Wakamatsu, K, Ito, S, Hearing, V, Kraemer, KH,
and Brash, DE. Melanin acts as a potent UVB sensitizer to cause an
atypical mode of cell death in murine skin. Proc. Natl. Acad. Sci. USA,
101:15076-15081, 2004.
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| Wikonkal, NM, Remenyik, E, Knezevic, D., Zhang, W, Liu, M, Zhou, H, Berton, TR, Johnson,
DG, and Brash, DE. Inactivating E2f1 reverts apoptosis resistance and cancer sensitivity in
Trp53-deficient mice. Nature Cell Biol. 5:655-660, 2003
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| Contact Information: | | |
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