Growth factors play good cop, bad cop
A basic cellular element playing a role in both normal development and malignant expression is transforming growth factor-beta (TGFb). TGFb is a small cell-signalling protein molecule, termed a cytokine, implicated in autoimmune diseases, developmental disorders, fibrosis and cancer. Its multifunctional nature sees it acting in both tumour suppression and progression. Although TGFb restricts the growth of early carcinomas, during tumour growth it can activate a transformation of epithelial cells to mesenchymal cells. This gives rise to an invasive, metastatic tumour situation. The cytokine signals through the activation of Smad proteins, which then gather in the nucleus. Here, they positively or negatively regulate transcription, but the process by which this happens remains unclear. The 'Regulating TGF-beta signalling at the transcriptional level and in cancer' (TGF-beta and cancer) project aimed to throw light on how TGFb regulates inhibition of bone morphogenetic protein (BMP)-induced transcription. BMPs are a cluster of growth factors that belong to the TGFb superfamily. When their signalling system is misregulated, cancer often follows shortly after. A second objective was to identify how Smad7 gives rise to heightened risk for colon cancer. Smads are proteins in cells that have been identified as mediators of transcriptional activation. During the course of the project, team members discovered it would be technically impossible to follow through on this second objective. Studies revealed that TGFb rapidly halts BMP-induced transcription. This was far from an expected finding. Further studies showed that this mechanism is independent of new protein synthesis. BMP signalling brings on the phosphorylation and nuclear accumulation of Smad1/5/8, whereas TGFb brings about the activation and nuclear accumulation of Smad2/3. In the nucleus, these form complexes with Smad4. The study found that even in the presence of over-expressed Smad4, TGFb could still restrain BMP signalling. TGFbs and BMPs play critical roles in maintaining the well-functioning status of adult tissue. Disturbance in these pathways manifests in several human disorders ranging from cancer to fibrosis.
