Lysyl oxidase like 4, a novel target gene of TGF-{beta}1 signaling, can negatively regulate TGF-{beta}1-induced cell motility in PLC/PRF/5 hepatoma cells

• Published in: Biochemical and biophysical research communications 2008-09, Vol.373 (4)
• Main Authors: Kim, Dong Joon, College of Pharmacy, Chungnam National University, Daejeon 305-764, Lee, Dong Chul, Yang, Suk-Jin, Lee, Jung Ju, Bae, Eun Mi, Kim, Dong Min, Min, Sang Hyun, Kim, Soo Jung, Kang, Dong Chul, Sang, Byung Chan, Myung, Pyung Keun, Park, Kyung Chan, Yeom, Young Il
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; CELL PROLIFERATION; CHROMATIN; GENE REGULATION; GROWTH FACTORS; HEPATOMAS; LIVER; METABOLISM; OXIDASES; PROMOTERS; TRANSCRIPTION FACTORS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.06.071

Transforming growth factor-{beta}1 (TGF-{beta}1) is a multi-functional cytokine involved in the regulation of cell proliferation, differentiation and extracellular matrix formation. In search for novel genes mediating the TGF-{beta}1 function at downstream signaling, we performed a cDNA microarray analysis and identified 60 genes whose expression is regulated by TGF-{beta}1 in the liver cancer cell line PLC/PRF/5. Among them, we report here lysyl oxidase like 4 (LOXL4) as a novel target of TGF-{beta}1 signaling, and provide experimental evidence for its expression regulation and function. LOXL4 was found to be the only member of LOX family whose expression is induced by TGF-{beta}1 in hepatoma cells. Deletion mapping of the LOXL4 promoter indicated that the TGF-{beta}1 regulation of LOXL4 expression is mediated through the binding of AP1 transcription factor to a conserved region of the promoter. This was confirmed by the chromatin immunoprecipitation assay that captured c-Fos-bound chromatin from TGF-{beta}1-treated cells. Forced expression of LOXL4 in PLC/PRF/5 cells resulted in inhibition of cell motility through Matrigel in the presence of TGF-{beta}1 treatment. In parallel, LOXL4 suppressed the expression of laminins and {alpha}3 integrin and the activity of MMP2. These results suggest that LOXL4 may function as a negative feedback regulator of TGF-{beta}1 in cell invasion by inhibiting the metabolism of extracellular matrix (ECM) components.