Scientists at the Burnham Institute for Medical Research have taken a step further in the fight against skin cancer by providing genetic evidence that Activating Transcription Factor 2 (ATF2) plays a suppressor role in the development of the disease.
ATF2 is a protein that regulates gene transcription, which is the first step in the translation of genetic code, in response to extra cellular stresses such as ultraviolet light and ionizing radiation.
This function of ATF2 in stress and DNA damage response indicates that it may also play a role in the formation of tumours.
Earlier studies led by Ze'ev Ronai, Ph.D. have suggested an important role of ATF2 in melanoma development and progression.
In this new study, the Ronai laboratory, together 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, tumours appeared faster and more frequently.
The team says that their findings reveal that loss of ATF2 transcriptional activity in skin exposed to carcinogens enhances skin tumour formation, suggesting a tumour suppressor role for ATF2 in keratinocytes.
"Important support for the finding comes from the analysis of tumour 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," he added.
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 tumour 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 tumour development; thus providing an example of a mechanism by which ATF2 functions as a tumour suppressor.
The study is published in Proceedings of the National Academy of Sciences of the United States of America.