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

Park, Yun Jong; Ahn, Hyung Joon; Kim, Yu Seun; Cho, Yuri; Joo, Dong Jin; Ju, Man Ki

doi:10.1016/j.cellsig.2010.07.005

Cited by 9 publications

(9 citation statements)

References 38 publications

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“…2a,c–e,f,h–j). To rule out the possibility that the results were due to an off target effect of the shRNA sequence, we repeated the experiments using a second RhoGDIα shRNA (shRhoGDIα#2)32. The results were similar to those with the first shRNA sequence, confirming that RhoGDIα downregulation reduces Cdc42, RhoA, and Rac1 in both hippocampal and cortical neurons (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 61%

Activating Transcription Factor 4 (ATF4) modulates Rho GTPase levels and function via regulation of RhoGDIα

Pasini

Liu

Corona

et al. 2016

Sci Rep

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In earlier studies, we showed that ATF4 down-regulation affects post-synaptic development and dendritic spine morphology in neurons through increased turnover of the Rho GTPase Cell Division Cycle 42 (Cdc42) protein. Here, we find that ATF4 down-regulation in both hippocampal and cortical neuron cultures reduces protein and message levels of RhoGDIα, a stabilizer of the Rho GTPases including Cdc42. This effect is rescued by an shATF4-resistant active form of ATF4, but not by a mutant that lacks transcriptional activity. This is, at least in part, due to the fact that Arhgdia, the gene encoding RhoGDIα, is a direct transcriptional target of ATF4 as is shown in ChIP assays. This pathway is not restricted to neurons. This is seen in an impairment of cell migration on ATF4 reduction in non-neuronal cells. In conclusion, we have identified a new cellular pathway in which ATF4 regulates the expression of RhoGDIα that in turn affects Rho GTPase protein levels, and thereby, controls cellular functions as diverse as memory and cell motility.

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Section: Resultsmentioning

confidence: 61%

Activating Transcription Factor 4 (ATF4) modulates Rho GTPase levels and function via regulation of RhoGDIα

Pasini

Liu

Corona

et al. 2016

Sci Rep

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“…As DAMTC downregulates the expression of RhoGDI α , it emphasizes its potential as an anti-cancer drug. Literature suggests that signals transmitted through Rho family GTPase are coupled to MAPK pathway, 17, 18, 19 and our previous study, as well as IPA analysis, shows that MAPK has a role in DAMTC-induced apoptosis, thus suggesting that Rho family GTPases could be the central target molecule of DAMTC responsible for its action.…”

Section: Discussionmentioning

confidence: 55%

DAMTC regulates cytoskeletal reorganization and cell motility in human lung adenocarcinoma cell line: an integrated proteomics and transcriptomics approach

et al. 2012

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DAMTC (7,8-diacetoxy-4-methylcoumarin) is a thioderivative of 4-methyl coumarin, and previously we have shown that DAMTC is a potent inhibitor of cell growth and an inducer of apoptosis in non-small cell lung cancer (A549) cells. It induces apoptosis through mitochondrial pathway by modulating NF-κB, mitogen-activated protein kinase (MAPK) and p53 pathways. Herein, we explored the genome-wide effects of DAMTC in A549 cells using the concerted approach of transcriptomics and proteomics. In addition to apoptotic pathways, which have been validated earlier, the bioinformatic analysis of microarray data identified small GTPase-mediated signal transduction among the significantly altered biological processes. Interestingly, we observed significant downregulation of some members of the Rho family GTPases in the proteomics data too. Downregulation of Rho GTPases (RhoGDIα (Rho GDP dissociation inhibitor-α, also known as ARHGDIA), Ras homolog family member A, Ras-related C3 botulinum toxin substrate 1 and cell division cycle 42) was validated by western blotting. The Rho protein family is implicated in maintaining the actin filament assembly and cell motility, and we also observed that DAMTC treatment causes actin cytoskeletal reorganization, promotes filopodia formation and inhibits cell motility in A549 cells. The effect of DAMTC treatment on cytoskeleton was reversed after the overexpression of RhoGDIα. In addition, DAMTC augmented the apoptotic effect of etoposide, a proapoptotic chemotherapeutic drug. This elucidation of the mechanism behind DAMTC-induced apoptosis and inhibition of cell motility in A549 cells may make it a potential therapeutic for lung cancer.

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“…13 For this analysis, INS-1E cells and isolated primary islets from rats were treated with 40 μ M MPA for 24 h or 48 h. INS-1E cells and isolated islets were analyzed using an Illumina RatRef-12 Expression BeadChip. Previous analysis identified genes related to the apoptosis signaling pathway and showed that decreased RhoGDI- α to Rac1 binding increased Rac1 activity.…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported the specific depletion of GTP via the MPA-induced apoptosis of insulin-secreting cells (HIT-T15, RIN-5, INS-1E, and isolated rat islets) and also confirmed that co-treatment with GTP completely blocked MPA-induced cell death, which suggest that MPA inhibits de novo GTP synthesis and depletes GTP. 11, 12, 13 In addition, we identified genes expressionally altered during MPA-induced β -cell death and grouped these genes by cellular function. In particular, the expressions of 386 genes in INS-1E cells and of 234 genes in primary rat islet cells were found to be significantly altered by MPA as determined using an Illumina cDNA microarray.…”

mentioning

confidence: 99%

“…In particular, the expressions of 386 genes in INS-1E cells and of 234 genes in primary rat islet cells were found to be significantly altered by MPA as determined using an Illumina cDNA microarray. 13 Further, the expressions of some genes, such as, RhoGDI-α , Thioredoxin 1 ( Trx1 ), Bcl2-related protein, and programmed cell death 2 (pdcd 2) , are known to be closely related to MPA-induced β -cell death. 13, 14, 15 …”

mentioning

confidence: 99%

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The role of thioredoxin 1 in the mycophenolic acid-induced apoptosis of insulin-producing cells

Huh

Cho

et al. 2013

Cell Death Dis

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Mycophenolic acid (MPA) is one of many effective immunosuppressive drugs. However, MPA can induce cellular toxicity and impair cellular function in β-cells. To explore the effects of MPA and the relation between MPA and Trx-1, we used various methods, including an Illumina microarray, to identify the genes regulated during pancreatic β-cell death following MPA treatment. INS-1E cells (a pancreatic β-cell line) and isolated rat islets were treated with MPA for 12, 24, or 36 h, and subsequent microarray analysis showed that (Trx1) gene expression was significantly reduced by MPA. Further, Trx1 overexpression increased the cell viability, decreased the activations of c-jun N-terminal kinase (JNK) and caspase-3 by MPA, and attenuated ROS upregulation by MPA. Furthermore, siRNA knockdown of Trx1 increased MPA-induced cell death and the activations of p-JNK and caspase-3, and MPA significantly provoked the apoptosis of insulin-secreting cells via Trx1 downregulation. Our findings suggest that the prevention of Trx1 downregulation in response to MPA is critical for successful islet transplantation.

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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

Cited by 9 publications

References 38 publications

Activating Transcription Factor 4 (ATF4) modulates Rho GTPase levels and function via regulation of RhoGDIα

Activating Transcription Factor 4 (ATF4) modulates Rho GTPase levels and function via regulation of RhoGDIα

DAMTC regulates cytoskeletal reorganization and cell motility in human lung adenocarcinoma cell line: an integrated proteomics and transcriptomics approach

The role of thioredoxin 1 in the mycophenolic acid-induced apoptosis of insulin-producing cells

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