Thioredoxin modulates activator protein 1 (AP-1) activity and p27Kip1 degradation through direct interaction with Jab1.
Thioredoxin (Trx) is a cellular redox enzyme that plays multiple roles in regulating cell growth and apoptosis. Jun activation domain-binding protein 1 (Jab1) was originally identified as a coactivator of activator protein 1 (AP-1) transcription and was also shown to promote degradation of the cyclin-dependent kinase inhibitor, p27Kip1. Recently, Jab1 expression was associated with the progression and poor prognosis of pituitary, epithelial ovarian, and breast cancers, suggesting that it plays a role in oncogenesis. Here, we report that Trx specifically interacts with and modulates the function of Jab1. Fluorescence resonance energy transfer and co-immunoprecipitation studies revealed that Trx and Jab1 colocalize and directly interact with each other. Further, Trx negatively regulates two important Jab1-controlled signaling pathways, activation of AP-1 transcription and degradation of p27Kip1, probably through a direct interaction between Trx and C-terminal of Jab1. The negative effect of Trx on AP-1 activity is Jab1-dependent, as it disappears when Jab1 levels are suppressed by an antisense approach. In addition, Trx competes with p27Kip1 for Jab1 binding. Taken together, our results suggest that Trx may regulate cell cycle and growth through a novel modulation of Jab1-mediated proliferation signals, further indicating that Trx may have the ability to control tumor progression.
Hwang
Chae Young
CY
Center for Systems Biology, Korea Research Institute of Bioscience and Biotechnology, Taejon 305-333, Korea.
Ryu
Yeung Sook
YS
Chung
Mi-Sun
MS
Kim
Kwang Dong
KD
Park
Sung Sup
SS
Chae
Suhn-Kee
SK
Chae
Ho Zoon
HZ
Kwon
Ki-Sun
KS
D001665:Binding Sites; D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003545:Cysteine / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D004220:Disulfides; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010084:Oxidation-Reduction; D010447:Peptide Hydrolases; D011379:Prognosis; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004220:Disulfides; D047908:Intracellular Signaling Peptides and Proteins; D016376:Oligonucleotides, Antisense; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013879:Thioredoxins; D005982:Glutathione Transferase; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D003545:Cysteine