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.
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.
Park
Yun-Jong
YJ
The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Republic of Korea.
Ahn
Hyung Joon
HJ
Kim
Yu Seun
YS
Cho
Yuri
Y
Joo
Dong Jin
DJ
Ju
Man Ki
MK
D000818:Animals; D017209:Apoptosis; D005786:Gene Expression Regulation; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D009173:Mycophenolic Acid / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D020730:Guanine Nucleotide Dissociation Inhibitors; D007328:Insulin; D034741:RNA, Small Interfering; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D009173:Mycophenolic Acid