The Molecular Mechanism of How Furin Is Regulated by Thyroid Hormone and Transforming Growth Factor-beta 1

• Main Authors: lin ya chu, 林亞筑
• Other Authors: 林光輝
• Format: Others
• Language: zh-TW
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/02352290800509854576

碩士 === 長庚大學 === 基礎醫學研究所 === 93 === The thyroid hormone, 3, 3', 5-triiodo-L-thyronine (T3) regulates cell growth, differentiation and development mediated by the nuclear thyroid hormone receptors (TRs), which belongs to the steroid/thyroid hormone receptor superfamily of ligand-dependent transcription factors. To study the mechanism of T3 regulated downstream genes in TR-overexpressed hepatoma cell line (HepG2-TR), cDNA microarrays analysis were performed. Approximately 201 of 7600 genes (2.6%) were positively regulated by T3 , furin is one of these up-regulated gene. Furin is a serine protease member of the family of proprotein-convertases (PCs) that catalyze the hydrolytic cleavage at the C-terminus of the motif RR/KXR. Many inactive proteins, including metalloproteinases, growth factors and growth factor receptors, contain this motif and become activated after furin-dependent proteolysis. One of furin substrate: TGFβ1 is known that regulates gene expression of its own converting enzyme Furin. Expression of furin is directed by multiple promoters including P1, P1A and P1B. Promoter P1 has both a TATA and CCAAT element, but also contains low affinity SP1 binding site. The promoters P1A and P1B have a very high GC content and several SP1 elements, typical features of promoters of housekeeping genes. Furin was induced about 7~8 fold in HepG2-TR1 at protein level after 48 h T3 treatment, 16 fold induced by T3 and TGFβ1, and 3~4 fold induced by TGFβ1. Similar up-regulation was observed at mRNA level. Interestingly, enzyme activity assay showed that both T3 and TGFβ1 treated can elevate furin enzyme activity but not T3 alone. Cycloheximide couldn’t inhibit the induction of furin by T3, indicating that this regulation was direct. The promoter assay indicates that the thyroid hormone responsive elements (TRE) located within P1A promoter region. Altogether,our results indicate that T3 might play an important role in the expression of furin. However, the physiological significance of furin up-regulation needs a further investigation.