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The RhoGDI-alpha/JNK signaling pathway plays a significant role in mycophenolic acid-induced apoptosis in an insulin-secreting cell line

 Yun-Jong Park  ;  Hyung Joon Ahn  ;  Hye Kyung Chang  ;  Joon Ye Kim  ;  Kyu Ha Huh  ;  Myoung Soo Kim  ;  Yu Seun Kim 
 CELLULAR SIGNALLING, Vol.21(2) : 356-364, 2009 
Journal Title
Issue Date
Analysis of Variance ; Animals ; Apoptosis*/drug effects ; Base Sequence ; Caspase 3/metabolism ; Cell Line ; Electrophoresis, Gel, Two-Dimensional ; Guanine Nucleotide Dissociation Inhibitors/metabolism* ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/enzymology ; Insulin-Secreting Cells/metabolism* ; JNK Mitogen-Activated Protein Kinases/metabolism* ; Mycophenolic Acid/pharmacology* ; Proteomics ; Rats ; Signal Transduction/drug effects ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; rho-Specific Guanine Nucleotide Dissociation Inhibitors
Mycophenolic acid ; Insulin-secreting cells ; Apoptosis ; RhoGDI-α ; JNK
Mycophenolic acid (MPA)-induced beta-cell toxicity is an important factor for islet graft function. The signal transduction mechanisms underlying this process have not been fully explored. Using a proteomics approach, we examined protein expression patterns in MPA-treated RIN-5 cells and found that RhoGDI-alpha expression is altered by MPA-treatment. We examined the relationship between RhoGDI-alpha expression and activated JNK during MPA-induced apoptosis. Cells were treated with N-acetyl-cysteine (NAC), caspase inhibitor, JNK inhibitor, guanosine or GTP for 1 h before being treated with MPA. To investigate the regulatory effects of RhoGDI-alpha on JNK activity, we examined cells showing either elevated or reduced expression of RhoGDI-alpha as a result of transfection with cDNA or siRNA constructs, respectively. MPA significantly increased cell death, caspase-3 expression and JNK activation, but it decreased the expression of a protein spot 25 observed by two-dimensional electrophoresis. This protein 25 was identified as RhoGDI-alpha by mass spectrometry. MPA-induced cell death and down-regulation of RhoGDI-alpha were prevented by guanosine, GTP or a JNK inhibitor. However, MPA-induced cell death was partially restored by treatment with a caspase inhibitor, but not by NAC treatment. RhoGDI-alpha expression was not affected by treatment with NAC or caspase inhibitor. Over-expression of RhoGDI-alpha increased cell viability and decreased activated JNK expression following exposure to MPA, whereas knockdown of RhoGDI-alpha enhanced MPA-induced cell death and increased the activation of JNK. In conclusion, MPA induces significant apoptosis in insulin-secreting cells via down-regulation of RhoGDI-alpha linked with increased JNK expression. This RhoGDI-alpha/JNK pathway might be the focus of therapeutic target for the prevention of MPA-induced islet apoptosis.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Kim, Yu Seun(김유선) ORCID logo https://orcid.org/0000-0002-5105-1567
Kim, Joon Ye(김준예)
Chang, Hye Kyung(장혜경)
Huh, Kyu Ha(허규하) ORCID logo https://orcid.org/0000-0003-1364-6989
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