Loss of metal transcription factor‐1 suppresses tumor growth through enhanced matrix deposition

• Published in: The FASEB journal Vol. 18; no. 11; pp. 1176 - 1184
• Main Authors: Haroon, Zishan A., Amin, Khalid, Lichtlen, Peter, Sato, Barbara, Huynh, Nhung T., Wang, Zhaohui, Schaffner, Walter, Murphy, Brian J.
• Format: Journal Article
• Language: English
• Published: United States Federation of American Societies for Experimental Biology 01-08-2004
• Subjects: Animals; Cell Division - genetics; Cell Line, Transformed; Disease Progression; DNA-Binding Proteins; Enzyme Induction; Extracellular Matrix - metabolism; Fibrinolysin - analysis; Fibroblasts - pathology; Fibroblasts - transplantation; Fibrosarcoma - blood supply; Fibrosarcoma - metabolism; Fibrosarcoma - pathology; Fibrosis; Genes, ras; GTP-Binding Proteins - biosynthesis; GTP-Binding Proteins - genetics; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; MTF-1; Neoplasm Transplantation; Neovascularization, Pathologic - genetics; Protein Glutamine gamma Glutamyltransferase 2; Transcription Factor MTF-1; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - physiology; Transforming Growth Factor beta - biosynthesis; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta1; Transglutaminases - biosynthesis; Transglutaminases - genetics; tumorigenesis
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.03-1205com

ABSTRACT
Metal transcription factor‐1 (MTF‐1) is a ubiquitous transcriptional regulator and chromatin in‐ sulator with roles in cellular stress responses and em‐ bryonic development. The studies described herein establish for the first time the involvement of MTF‐1 in tumor development. Genetically manipulated ras‐trans‐ formed mouse embryonic fibroblasts (MEFs), wild‐type (MTF‐1+/+), or nullizygous for MTF‐1 (MTF‐1‒/‒) were used to develop fibrosarcoma tumors. Loss of MTF‐1 resulted in delayed tumor growth associated with increased matrix collagen deposition and reduc‐ tions in vasculature density. Molecular consequences of MTF‐1 loss include increased expression and activation of the transforming growth factor–β1 (TGF‐β1) and tissue transglutaminase (tTG), two proteins with docu‐ mented roles in the production and stabilization of extracellular matrix (ECM). Our findings support the hypothesis that MTF‐1 enhances the ability of the developing tumor mass to evade fibrosis and scarring of the tumor, a critical step in tumor cell prolifera‐ tion.—Haroon, Z. A., Amin, K., Lichtlen, P., Sato, B., Huynh, N. T., Wang, Z., Schaffner, W., Murphy, B. J. Loss of metal transcription factor‐1 suppresses tumor growth through enhanced matrix deposition. FASEB J. 18, 1176 –1184 (2004)