Identification of TGF-β1-dependent signalling cascades mediating radiation- induced ATM activity

Over the recent years our laboratory could demonstrate that the radiation-induced terminal differentiation of the fibroblast cell system, i.e. the induced differentiation of progenitor fibroblasts to postmitotic highly collagen synthesizing fibrocytes, is the key event in the induction and manifestation of the fibrotic tissue remodelling mainly independent of the radiation quality used. Molecular biological studies into the basic mechanisms of radiation, i.e. photon and heavy ion radiation induced terminal fibroblast differentiation revealed that the cytokine TGF-β1 is a key mediator regulating radiation-induced differentiation [1]. As a consequence of both photon and heavy ion irradiation in the previous research period, it could be postulated that radiation (photon and heavy ion radiation) rather leads to the proteolytic activation of latent TGF-β1 (LTGF-β1) to the active form of this cytokine than to a stimulation of gene expression [2]. For practical reasons, this hypothesis was tested first in photon-irradiated cells by the use of a specific inhibitor of the protease furin, which is known to be a major component of the proteolytic activation process of LTGF-β1 to TGF-β1. Preincubation with the furin inhibitor CMK resulted in a significant decrease of the phosphorylation of Smad-2 and – 3 proteins involved in the intracellular TGF-β1 receptordependent signal transduction. Although not yet analyzed, it can be assumed that heavy ion irradiation will lead to a similar effect if not more pronounced activation of LTGFβ1 as shown for photon irradiation [2].