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.
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.
Kim
Dong Joon
DJ
Medical Genomics Research Center, KRIBB, P.O. Box 115, Yusong, Daejeon 305-806, Republic of Korea.
Lee
Dong Chul
DC
Yang
Suk-Jin
SJ
Lee
Jung Ju
JJ
Bae
Eun Mi
EM
Kim
Dong Min
DM
Min
Sang Hyun
SH
Kim
Soo Jung
SJ
Kang
Dong Chul
DC
Sang
Byung Chan
BC
Myung
Pyung Keun
PK
Park
Kyung Chan
KC
Yeom
Young Il
YI
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
D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D000594:Amino Acid Oxidoreductases; C445682:LOXL4 protein, human; D008249:Protein-Lysine 6-Oxidase