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Illumina-microarray analysis of mycophenolic acid-induced cell death in an insulin-producing cell line and primary rat islet cells: new insights into apoptotic pathways involved

 Yun-Jong Park  ;  Hyung Joon Ahn  ;  Yu Seun Kim  ;  Yuri Cho  ;  Dong Jin Joo  ;  Man Ki Ju 
 CELLULAR SIGNALLING, Vol.22(11) : 1773-1782, 2010 
Journal Title
Issue Date
Animals ; Apoptosis* ; Gene Expression Regulation ; Guanine Nucleotide Dissociation Inhibitors/genetics ; Guanine Nucleotide Dissociation Inhibitors/metabolism ; Insulin/metabolism ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism* ; Islets of Langerhans/drug effects ; Islets of Langerhans/metabolism* ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Mycophenolic Acid/toxicity* ; Oligonucleotide Array Sequence Analysis ; RNA Interference ; RNA, Small Interfering/metabolism ; Rats ; rac1 GTP-Binding Protein/metabolism ; rho-Specific Guanine Nucleotide Dissociation Inhibitors
Mycophenolic acid ; INS-1E ; Islet cells ; Apoptosis ; RhoGDI-α ; Rac1
Mycophenolic acid (MPA), widely used to prevent organ transplant rejection, may induce toxicity and impair function in beta-cells. Mechanisms of MPA-induced cell death have not been fully explored. In this study, we examined gene expression patterns in INS-1E cells and isolated primary rat islets following MPA treatment using the Illumina-cDNA microarray. The MPA treatment decreases RhoGDI-alpha gene expression, which points to apoptosis by JNK activation through a MAPKs-dependent pathway. A strong association between RhoGDI-alpha and Rac1 activation during MPA-induced apoptosis is also consistent with apoptosis through JNK. Suppression of RhoGDI-alpha using siRNA and gene over-expression both affected the cell death rate, consistent with Rac1 activation and downstream activation of MAPKs signaling. We confirmed that Rac1 protein mediates the interaction between RhoGDI-alpha and JNK signaling. We conclude that MPA-induced cell death in primary beta-cells and an insulin-secreting cell line proceeds through RhoGDI-alpha down-regulation linked to Rac1 activation, with subsequent activation of JNK. The RhoGDI-alpha/Rac1/JNK pathway may present a key to intervention in MPA-induced islet apoptosis.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
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, Yu Seun(김유선) ORCID logo https://orcid.org/0000-0002-5105-1567
Park, Yun Jong(박윤종)
Cho, Yu Ri(조유리)
Joo, Dong Jin(주동진) ORCID logo https://orcid.org/0000-0001-8405-1531
Joo, Man Ki(주만기) ORCID logo https://orcid.org/0000-0002-4112-7003
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