Signalling by TGF-β family members in early vertebrate development and in tumorigenesis
Previous and current research
Members of the transforming growth factor-β (TGF-β) superfamily regulate many key events of early vertebrate embryogenesis and are involved in tissue homeostasis in adult organisms. Moreover, TGF-β1, the prototype of the family, plays important roles in tumorigenesis, acting as a tumour suppressor at early stages and as a tumour promoter at later stages. Signals from TGF-β superfamily receptors are transduced to the nucleus primarily by the Smads, which are activated in response to receptor stimulation and act directly in the nucleus in conjunction with other transcription factors to regulate transcription of target genes. We aim to understand the role of TGF-β in tumorigenesis, and also the role of related ligands in early vertebrate development, using predominantly Xenopus as an experimental system.
From our work in both Xenopus embryos and mammalian cells we have gained important insights into the mechanisms that determine the specificity of the downstream responses and into the basic regulatory mechanisms of signalling. We have shown that signal duration plays an important role in determining the specificity of the biological response to ligand stimulation, as well as the cell type specific transcription factors that recruit activated Smads to promoters of target gene. We have demonstrated that constant nucleocytoplasmic shuttling of the Smads during active signalling provides a mechanism whereby the intracellular transducers of the signal continuously monitor the duration of receptor activity, and we have now defined the mechanisms whereby Smad nucleocytoplasmic shuttling is regulated. We have recently determined how Smads regulate transcriptional activation through chromatin remodelling. We are beginning to understand how TGF-β signalling may be perturbed during tumour development and progression.
Future projects
We will use Xenopus and zebrafish embryos to understand the mechanisms underlying the dose-dependent effects of TGF-β superfamily ligands and to visualise the dynamics of signalling. We will continue to study the basic regulatory mechanisms of signalling, and to investigate how Smads regulate transcription of target genes. We aim to identify novel components of the signalling pathways using high-throughput siRNA screens in tissue culture cells and expression screens in Xenopus. In the context of tumorigenesis, we want to understand how tumour cells become resistant to the tumour suppressive effects of TGF-β and instead become de-differentiated, invasive and metastatic in response to this ligand. We will study this in model tissue culture systems and also in mouse models.
