title: Lysyl oxidase like 4, a novel target gene of TGF-beta1 signaling, can negatively regulate TGF-beta1-induced cell motility in PLC/PRF/5 hepatoma cells.
abstract: Transforming growth factor-beta1 (TGF-beta1) 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-beta1 function at downstream signaling, we performed a cDNA microarray analysis and identified 60 genes whose expression is regulated by TGF-beta1 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-beta1 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-beta1 in hepatoma cells. Deletion mapping of the LOXL4 promoter indicated that the TGF-beta1 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-beta1-treated cells. Forced expression of LOXL4 in PLC/PRF/5 cells resulted in inhibition of cell motility through Matrigel in the presence of TGF-beta1 treatment. In parallel, LOXL4 suppressed the expression of laminins and alpha3 integrin and the activity of MMP2. These results suggest that LOXL4 may function as a negative feedback regulator of TGF-beta1 in cell invasion by inhibiting the metabolism of extracellular matrix (ECM) components.
authors.affiliation: Medical Genomics Research Center, KRIBB, P.O. Box 115, Yusong, Daejeon 305-806, Republic of Korea.
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Dong Chul
authors.initials: DC
authors.lastname: Lee
authors.forename: Suk-Jin
authors.initials: SJ
authors.lastname: Yang
authors.forename: Jung Ju
authors.initials: JJ
authors.lastname: Lee
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Bae
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Kim
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Min
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Dong Chul
authors.initials: DC
authors.lastname: Kang
authors.forename: Byung Chan
authors.initials: BC
authors.lastname: Sang
authors.forename: Pyung Keun
authors.initials: PK
authors.lastname: Myung
authors.forename: Kyung Chan
authors.initials: KC
authors.lastname: Park
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism; D025461:Feedback, Physiological; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D008249:Protein-Lysine 6-Oxidase; D018808:Transcription Factor AP-1; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D000594:Amino Acid Oxidoreductases; C445682:LOXL4 protein, human; D008249:Protein-Lysine 6-Oxidase