Mechanisms of halofuginone activity
By: by Yana George Kamberov
Published: 2008
Language: eng
Number of pages: 146
Description: Aberrant deposition or remodeling of the extracellular matrix (ECM) is a cause of a wide range of human pathologies, including fibrosis and tumorigenesis. The small molecule Halofuginone (HF) is a potent and specific regulator of ECM gene expression and is unique in its therapeutic potential. The basis for HF effects on the ECM is unknown but ultimately results in the transcriptional control of a number of ECM components including Type I collagen. The aim of this study was to identify the molecular mediators of HF function in order to elucidate the mechanism by which the compound exerts biological effects. We have synthesized active and inactive variants of HF, and have used derivatized HF as the basis for a novel polymer-based affinity purification technique to identify the transcriptional co-repressor TRIM28 as the first specific HF binding protein. We show that TRIM28 is required for the transcriptional regulation of a subset of HF target genes and that HF treatment alters the sumoylation state of TRIM28. Moreover, using microarray expression analysis, we report the first early, global transcriptional profile for HF, which suggests several novel mechanisms for HF activity. In contrast to the currently accepted model for HF action, our findings point away from a central role of TGFβ signaling in the HF mechanism of actions and suggest a new approach to small molecule based regulation of the ECM transcriptional program in vivo . In addition, our affinity purification system provides an improvement over existing approaches for the identification of new cellular targets of small molecules. Finally, knowing the molecular targets of HF allows the development of more specific and better tailored therapeutics, and provides a powerful tool for elucidating ECM biology on the sub-cellular level.
Notes: "May 2008."

Thesis (Ph.D., Division of Medical Sciences (Cell and Developmental Biology))--Harvard University, 2008.

Includes bibliographical references.