The photodamage response plays a protective role against cancer development in skin. It orchestrates tissue repair by recovering lightly damaged cells and at the same time eliminates mutated cells with oncogenic potential. Cellular sensors are poised to advance either DNA repair pathways or apoptosis cascades in response to different levels of UV-induced damage. The molecules that integrate the cellular signals from a recovering cell and decide its fate are not fully understood. A potentially important regulator of the photodamage response is the Bcl-2, """"""""BH3-only"""""""" family member, Bid. Bid is a well-known initiator of the mitochondrial pathway of apoptosis. Paradoxically, Bid also possesses a prosurvival function for cell recovery by activating a cell cycle checkpoint during S-phase. These opposing activities are performed by distinctly different posttranslational modifications of Bid - a phosphorylated form (pBid) that acts in the nucleus or a truncated form (tBid) that targets the mitochondrion. The dual functions of Bid have some similarities to the tumor suppressor p53, the best-known regulator of cell fate. We have established that UV radiation can induce the prosurvival form, pBid, in mouse and human skin cells. Furthermore, we have evidence that Bid is a tumor suppressor. Bid's role in promoting cell survival has not been determined in the epidermal response to UV irradiation. This proposal will test the hypothesis that Bid plays a critical role in keratinocyte UVB photodamage responses by promoting either DNA repair or apoptosis. We will determine the extent to which pBid performs S-phase checkpoint function in both mouse and human cells. Further, we will evaluate the roles of the UV-DNA damage kinase ATR, and p53 in regulating Bid function. We will examine the tumorigenic potential of Bid deficient cells as well as cells reconstituted with both WT and mutant forms of Bid to determine whether its tumor suppressor activity maps to cell survival or apoptotic functions. We will also create a new mouse model to assess Bid's role as tumor suppressor in the development of squamous cell carcinoma.
The specific aims are as follows: 1. To determine the role of Bid in promoting DNA repair in UVB damaged skin cells. 2. To determine the impact of Bid deficiency on the development of UV-induced cutaneous tumors.

Public Health Relevance

Ultraviolet (UV) light from the sun is a potent carcinogen because it introduces mutations in the DNA and causes cell damage. We will investigate a novel tumor suppressor function exhibited by a molecule called Bid, with specific focus on its proposed role in cell-cycle checkpoint activity that is activated by UV radiation, and its role in suppressing the development of UV-induced tumors. The results from these studies may uncover a new mechanism for controlling cancer and a possible new target for diagnostic or therapeutic applications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AR055252-02
Application #
7908747
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Baker, Carl
Project Start
2009-08-05
Project End
2013-07-31
Budget Start
2010-08-01
Budget End
2013-07-31
Support Year
2
Fiscal Year
2010
Total Cost
$228,430
Indirect Cost
Name
University of Alabama Birmingham
Department
Dermatology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Nasti, Tahseen H; Timares, Laura (2015) MC1R, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer. Photochem Photobiol 91:188-200
Beatty, M S; Timares, L; Curiel, D T (2013) Augmented adenovirus transduction of murine T lymphocytes utilizing a bi-specific protein targeting murine interleukin 2 receptor. Cancer Gene Ther 20:445-52
Hangalapura, Basav N; Timares, Laura; Oosterhoff, Dinja et al. (2012) CD40-targeted adenoviral cancer vaccines: the long and winding road to the clinic. J Gene Med 14:416-27
Nasti, Tahseen H; Timares, Laura (2012) Inflammasome activation of IL-1 family mediators in response to cutaneous photodamage. Photochem Photobiol 88:1111-25