BMB Section seminar: “Transcriptional Networks Co-operate to Orchestrate the Stem Cell Compartment in the GI Crypt & in Cancer”
Professor Robert George Ramsay
Group Leader, (SPRF. Level E) Peter MacCallum Cancer Centre; Full Professor, The Sir Peter MacCallum Oncology Department, University of Melbourne, NHMRC SRF(B), Australia
Robert G. Ramsay (Photo: Private)
The intestinal crypt stem cell (ISC) population is cast with the life-long role of replenishing the gastrointestinal tract (GIT) mucosa every 3-4 days. If this was not enough of a responsibility there is also the task of responding to extrinsic damage following mucosal damage as a result of cytotoxic insults associated with infection, inflammation and chemo and radiotherapy. Central to this capacity is the network of transcription factors which co-ordinate the transcriptome underpinning both homeostasis and emergency responses. In an attempt to understand these networks we have employed in vitro and in vivo mouse model systems in reference to these transcription pathways noting those that are commonly activated in GI cancer. Importantly, we have deliberately examined these pathways together rather than in singularity, and also not simply in absentia (ie. by knockout studies). Five transcription factors will be considered; NFkB, STAT3, MYB, b-catenin/TCF4 and NOTCH1. Although not an exhaustive list we have found that these factors are substantially responsible for the dynamic responses of ISC to the life-long demands of the normal GI mucosa. In addition, from these studies we have a greater insight into the hierarchy and interplay between the signalling pathways that activate these transcriptional networks.