Project E

Role of TGF-β and the p53 family in normal tissue damage

Coordinator: M. Niemantsverdiet

The TGF-β pathway and the p53 family are both well known for their involvement in cancer. However, both also regulate transcription of genes involved in normal tissue damage after radiation. After radiation therapy, a large percentage of patients suffers from fibrosis (a form of normal tissue damage), induced in normal (non-cancerous) tissues, this can severely reduce the quality of life and even cause death. Because patients are genetically diverse, the intensity of normal tissue damage varies enormously between patients. In our research we would like to find out what the role of the TGF-β pathway and the p53 family is, which genes play a role in the normal tissue damage after irradiation caused by TGF-b and p53 family and which of these genes are variable and might thus cause the difference in fibrotic reaction between individual patients. The ultimate goal is to find a set of genes that can predict the fibrotic reaction of patients before radiotherapy so a prediction can be made which patients will suffer a lot from normal tissue damage (these patients can be treated with a lower dose to reduce normal tissue damage) or patients that are relatively immune for radiation (these can be given a relatively high dose, so the tumour will disappear more easily).

References:

1)Hageman J, Eggen BJ, Rozema T, Damman K, Kampinga HH, Coppes RP.

Radiation and transforming growth factor-beta cooperate in transcriptional activation of the profibrotic plasminogen activator inhibitor-1 gene.

Clin Cancer Res. 2005 Aug 15;11(16):5956-64.

2)Cordenonsi M, Dupont S, Maretto S, Insinga A, Imbriano C, Piccolo S.

Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads.

Cell. 2003 May 2;113(3):301-14.