Researchers at the Burnham Institute for Medical Research (Burnham Institute) have provided genetic evidence that Activating Transcription Factor 2 (ATF2) plays a suppressor role in skin cancer development. ATF2 is a protein that regulates gene transcription, which is the first step in the translation of genetic code, in response to extracellular stresses such as ultraviolet light and ionizing radiation. This function of ATF2 in stress and DNA damage response suggests that it may also play a role in the formation of tumors.
Previous studies led by Ze'ev Ronai, Ph.D. have suggested an important role of ATF2 in melanoma development and progression. In this new study, published in this week's issue of Proceedings of the National Academy of Sciences of the United States of America, the Ronai laboratory, in collaboration with Nic Jones, Ph.D. from the University of Manchester UK, used a mouse model that expresses a transcriptionally inactive form of ATF2 in skin cells (keratinocytes). When the mice were subjected to chemically mediated skin carcinogenesis, tumors appeared faster and more frequently. These findings reveal that loss of ATF2 transcriptional activity in skin exposed to carcinogens enhances skin tumor formation, suggesting a tumor suppressor role for ATF2 in keratinocytes.
"Important support for the finding comes from the analysis of tumor samples from human patients with non malignant skin cancer," states Dr. Ronai. "Unlike the strong nuclear expression of ATF2 in normal skin, squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) samples exhibit a significantly reduced nuclear staining for ATF2."
The analysis of human skin cell carcinomas are also consistent with the reduced expression of ATF2 found in the papillomas that developed in the wild-type animals in this study, supporting the notion that ATF2 needs to be inactivated to support skin tumor development.
The group also identified ATF2 as an upstream regulator of genes including Presenilin1 (PS1), Notch1, and â-catenin, all of which have previously been reported to be involved in skin tumor development; thus providing an example of a mechanism by which ATF2 functions as a tumor suppressor.
This research, performed by the Ronai laboratory, is supported by a grant from the National Cancer Institute of the National Institutes of Health.
About Burnham Institute for Medical Research
Burnham Institute for Medical Research conducts world-class collaborative research dedicated to finding cures for human disease, improving quality of life, and thus creating a legacy for its employees, donors, and community. The Institute is headquartered in La Jolla, CA where it was established as a nonprofit, public benefit corporation in 1976 and is now home to four major centers: a National Cancer Institute-designated Cancer Center; the Del E. Webb Center for Neurosciences, Aging and Stem Cell Research; the Infectious and Inflammatory Disease Center; and the Sanford Children's Health Research Center. In 2006,
Burnham established a center for bionanotechnology research at the University of California, Santa Barbara. Burnham is currently establishing a campus at Lake Nona in Orlando, Florida that will focus on diabetes and obesity research and will expand the Institute's drug discovery capabilities. Today, Burnham employs more than 800 people and ranks consistently among the world's top 25 organizations for its research impact and among the top four research institutes nationally for NIH grant funding. For additional information about Burnham and to learn about ways to support its research, visit www.burnham.org.