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MTF‐1 Contributes to the Activation of MMP‐2
Author(s) -
Amin Khalid,
Sato Barbara G,
Haroon Zishan A,
Murphy Brian J
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1097
Subject(s) - matrix metalloproteinase , extracellular matrix , microbiology and biotechnology , transcription factor , wild type , null cell , cancer research , biology , chemistry , cell culture , biochemistry , genetics , mutant , gene
We previously reported a unique role for the redox‐sensitive, metal‐responsive transcription factor‐1 (MTF‐1) in tumor development: loss of Mtf1 delays fibrosarcoma tumor growth, increases tumor collagen deposition, and increases expression and activation of tumor cell and whole tumor transforming growth factor and tissue transglutaminase, two pivotal profibrotic proteins. This ongoing study demonstrates another level of MTF‐1‐dependent control over extracellular matrix (ECM) remodeling. Using ras ‐transformed Mtf1 null mouse embryonic fibroblasts (MEFs) and retroviral rescue of Mtf1, we show that MTF‐1 is essential for optimal activation of matrix metalloproteinase (MMP)‐2. Loss of Mtf1 markedly reduced activated MMP‐2, while Mtf1 rescue partly restored the wild type phenotype. Conversely, levels of tissue inhibitor of metalloproteinase (TIMP)‐2 dramatically increased in Mtf1 null MEFs compared with wild type cells. Retroviral‐directed rescue of Mtf1 significantly reduced these levels. Since the membrane type 1‐metalloproteinase (MT1‐MMP; MMP‐14) forms a complex with TIMP‐2 and MMP‐2 in regulating activation of MMP‐2, we also assessed its levels as a function of MTF‐1 expression. Activity levels of MT1‐MMP were significantly higher in wild type fibroblasts than in the Mtf1 knockout MEFs. The precise underlying mechanisms of this MTF‐1‐dependent system are under investigation. Together, our data indicate a role for MTF‐1 in ECM remodeling and thus in important physiological and pathophysiological processes. This work was supported by NIH Grant CA 057692.