Dissecting the transcriptional mechanisms controlling growth during normal development and cancer

Projektinformationen

GROWTHCONTROL

ID Finanzhilfevereinbarung: 232989

Abgeschlossenes Projekt

Startdatum 1 März 2009

Enddatum 28 Februar 2014

Finanziert unter

• Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Gesamtkosten € 2 200 000,00

EU-Beitrag € 2 200 000,00

Koordiniert durch

KAROLINSKA INSTITUTET
Sweden

Final Report Summary - GROWTHCONTROL (Dissecting the transcriptional mechanisms controlling growth during normal development and cancer)

This project analyzed molecular mechanisms of growth control and cancer through the combined use of high-throughput technologies and computational biology. We aimed to create a systems-level understanding of the cell cycle, and its regulation by physiological growth factors and oncogenes through the use high-throughput biology to identify all or the majority of genes that are essential for cell cycle progression, and by combining this dataset with computationally predicted and experimentally validated target genes of growth factors and oncogenic pathways.

Specific objectives:
1 To identify genome-wide the genes and mechanisms that control the metazoan cell cycle
2 To understand the molecular basis of organ specific growth control

The project first focused on automated analyses that were used to generate large amounts of data that is important in understanding of gene regulation and control of cell growth. After the data generation phase, the data was analyzed and validated experimentally.
One of the main achievements of the project is the identification of binding specificities of transcription factors – the proteins that read the human genome. Determination of the sequence of the human genome, and knowledge of the genetic code through which mRNA is translated have allowed rapid progress in identification of mammalian proteins. However, less is known about the molecular mechanisms that control gene expression, and about the variations in gene expression that underlie many pathological states, including cancer. This has been caused in part by lack of information about the binding specificities of transcription factors. In this project, we have analyzed binding specificity of almost all human transcription factors, and have generated a large library of sequences that bind to transcription factors.
We further applied the knowledge of transcription factor binding specificities together with experimentally identified cell cycle regulators to find central target genes that control cell growth under physiological conditions and in cancer. We found two key transcriptionally controlled mechanisms, MYC and Cdk4/6 system, and validated a regulatory element upstream of the MYC gene in a knockout mouse model. The mice lacking the element were viable and fertile, but were resistant to intestinal tumorigenesis. Our results revealed an unexpected difference between normal growth control mechanisms and pathological growth induced by cancer that can be exploited in development of future cancer therapies.