The RhoGDI-α/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

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Mycophenolic acid (MPA)-induced β-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-α expression is altered by MPA-treatment. We examined the relationship between RhoGDI-α 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-α on JNK activity, we examined cells showing either elevated or reduced expression of RhoGDI-α 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-α by mass spectrometry. MPA-induced cell death and down-regulation of RhoGDI-α 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-α expression was not affected by treatment with NAC or caspase inhibitor. Over-expression of RhoGDI-α increased cell viability and decreased activated JNK expression following exposure to MPA, whereas knockdown of RhoGDI-α 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-α linked with increased JNK expression. This RhoGDI-α/JNK pathway might be the focus of therapeutic target for the prevention of MPA-induced islet apoptosis.

Original languageEnglish
Pages (from-to)356-364
Number of pages9
JournalCellular Signalling
Volume21
Issue number2
DOIs
Publication statusPublished - 2009 Feb

Bibliographical note

Funding Information:
This work was supported by a grant from The Korean Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (No. A080058) and by a faculty research grant of Yonsei University College of Medicine (No. 6-2007-0103) and further supported by 2007–9 unrestricted islet research grant-in-aid from National BK21 Project Team of Nanobiomaterials for Cell-Based Implants at Yonsei University.

All Science Journal Classification (ASJC) codes

  • Cell Biology

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