Microarray profiling reveals the integrated stress response is activated by halofuginone in mammary epithelial cells
1 Genetics Department, Harvard Medical School, Boston, MA, USA
2 Division of Biomedical Informatics, University of California, San Diego, CA, USA
3 Center for Systems Biology, Chemical Biology Platform, Massachusetts General Hospital, Boston, MA and Infectious Diseases Initiative, The Broad Institute of Harvard University and MIT, Cambridge, MA, USA
4 Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, MA, USA
5 Department of Developmental Biology, Harvard School of Dental Medicine, Boston MA, USA
BMC Research Notes 2011, 4:381 doi:10.1186/1756-0500-4-381Published: 5 October 2011
The small molecule Halofuginone (HF) is a potent regulator of extracellular matrix (ECM ) gene expression and is unique in its therapeutic potential. While the basis for HF effects is unknown, inhibition of TGFβ signaling and activation of the amino acid restriction response (AAR) have been linked to HF transcriptional control of a number of ECM components and amelioration of fibrosis and alleviation of autoimmune disease by regulation of Th17 cell differentiation, respectively. The aim of this study was to generate a global expression profile of HF targets in epithelial cells to identify potential mediators of HF function in this cell type.
We report that HF modulation of the expression of the ECM remodeling protein Mmp13 in epithelial cells is separable from previously reported effects of HF on TGFβ signal inhibition, and use microarray expression analysis to correlate this with transcriptional responses characteristic of the Integrated Stress Response (ISR).
Our findings suggest activation of the ISR may be a common mechanism underlying HF biological effects.