Effects of small interfering RNAs targeting MAPK1 on gene expression profile in HeLa cells as revealed by microarray analysis

Huang, Chen; Liu, Liying; Li, Zong-Fang; Wang, Pei; Ni, Lei; Song, Lingyun; Xu, Dehui; Song, Taek Lyul

doi:10.1016/j.cellbi.2008.04.019

Cited by 9 publications

(9 citation statements)

References 39 publications

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“…Importantly, most of these signals are derived from non-chr21 DEGs, and would be missed by analyses focused specifically on chr21-encoded genes (Figure 2A). This analysis also identified two known repressors of IFN signaling, MAPK1 and TRIM24, as upstream regulators inactivated in T21 cells, consistent with activation of the IFN pathway (Huang et al, 2008; Tisserand et al, 2011). As an example of how the RNA-seq data supports the upstream regulator prediction by IPA, Figure 2B shows the gene network centered on the ligand IFNA2 as a potential driver of consistent gene expression changes.…”

Section: Resultssupporting

confidence: 58%

Trisomy 21 consistently activates the interferon response

Sullivan¹,

Lewis²,

Hill³

et al. 2016

eLife

268

261

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Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits.DOI: http://dx.doi.org/10.7554/eLife.16220.001

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Section: Resultssupporting

confidence: 58%

Trisomy 21 consistently activates the interferon response

Sullivan¹,

Lewis²,

Hill³

et al. 2016

eLife

268

261

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“…Previously, Kalvakolanu and colleagues showed that upon IFNγ induction C/EBP-β is phosphorylated by MAPK1/2 to activate expression of the GATE-driven genes (Roy et al, 2002). However, this model does not explain up-regulation of the GATE-driven genes when only MAPK1 is knocked down in cells (Huang et al, 2008) or the suppression of IRF9 and OAS1 8 hours post IFNγ-treatment (Figure 5J). Based on the newly discovered DNA-binding activity of MAPK1, a plausible explanation is that expression of the GATE-driven genes is dictated by competitive binding of C/EBP-β and MAPK1 to GATE element.…”

Section: Discussionmentioning

confidence: 92%

“…To identify targets of MAPK1 and thereby gain clues to its function, we compared the gene-expression profiles of HeLa cells to those of the cells in which MAPK1 is knocked down using siRNA (Huang et al, 2008). Because MAPK1 showed a dose-dependent repression of luciferase activity in the assays described above, we collected the promoter sequences of 82 genes that showed at least a two-fold up-regulation of expression following siRNA-mediated knockdown of MAPK1 when compared to the control.…”

Section: Resultsmentioning

confidence: 99%

“…Based on the newly discovered DNA-binding activity of MAPK1, a plausible explanation is that expression of the GATE-driven genes is dictated by competitive binding of C/EBP-β and MAPK1 to GATE element. In untreated cells, GATE is directly bound by MAPK1 via its DNA-binding domain and transcription of the downstream genes is inhibited, which explains the up-regulation of those IFN-response genes when MAPK1 is knocked down (Huang et al, 2008). When cells are treated with IFNγ, C/EBP-β is rapidly induced and phosphorylated by MAPK1/2, which are activated by the MEKK1/MEK1 pathway (Roy et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Profiling the Human Protein-DNA Interactome Reveals ERK2 as a Transcriptional Repressor of Interferon Signaling

Xie

Onishi

et al. 2009

Cell

358

406

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SUMMARY Protein-DNA interactions (PDIs) mediate a broad range of functions essential for cellular differentiation, function, and survival. However, it is still a daunting task to comprehensively identify and profile sequence-specific PDIs in complex genomes. Here, we have used a combined bioinformatics and protein microarray-based strategy to systematically characterize the human protein-DNA interactome. We identified 17,718 PDIs between 460 DNA motifs predicted to regulate transcription and 4,191 human proteins of various functional classes. Among them, we recovered many known PDIs for transcription factors (TFs). We also identified a large number of new PDIs for known TFs, as well as for previously uncharacterized TFs. Remarkably, we found that over three hundred proteins not previously annotated as TFs also showed sequence-specific PDIs, including RNA binding proteins, mitochondrial proteins, and protein kinases. One of such unconventional DNA-binding proteins, MAPK1, acts as a transcriptional repressor for interferon gamma-induced genes.

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“…Previous studies showed that siRNA targeting for the MAPK p42 gene partially inhibits proliferation and increases apoptosis in human cervical carcinoma HeLa cells (18,19). Results of a microarray analysis showed that MAPK p42 siRNA inhibited cell growth through the regulation of cell cycle control and apoptosis and induced an interferon-like response in HeLa cells (20). In order to confirm the specific effects of siRNA on MAPK p42 and the non-specific interferon-like response effect, the roles of siRNA and U0126, an inhibitor of MAPK p42, were compared in HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

Small-interfering RNA-mediated silencing of the MAPK p42 gene induces dual effects in HeLa cells

Yuan

Liu²,

Wang³

et al. 2010

Oncology Letters

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Abstract. The genesis and progression of cervical cancer involve the mutation or deviant expression of numerous genes, including the activation of oncogenes (Ha-ras, C-myc, C-erbB2 and Bcl-2) and inactivation of tumor-suppressor genes (p53 and Rb). Previous studies showed that small-interfering RNAs (siRNAs) targeting the MAPK p42 gene partly inhibit proliferation and increase apoptosis in human cervical carcinoma HeLa cells. Results of a microarray analysis showed that MAPK p42 siRNA inhibited cell growth through the regulation of cell cycle control and apoptosis and induced interferon-like response in HeLa cells. In order to confirm the dual effects of MAPK p42 siRNA, we compared the roles of siRNA and U0126, an inhibitor of MAPK p42, in HeLa cells. Short 21-mer double-stranded/siRNAs were synthesized to target MAPK p42 mRNA in HeLa cells. The siRNAs were transfected into HeLa cells using Lipofectamine. The cells were treated with siRNA or U0126 at different concentrations for a period of 48 h. The biological effect of siRNA and U0126 on HeLa cells was measured by MTT and flow cytometry. MAPK1, NUP188, P38, STAT1, STAT2, PML and OAS1 were analyzed by real-time quantitative PCR. HeLa cell growth was inhibited by siRNA or U0126, and the effect of siRNA inhibition was greater than that of U0126. Cell cycle phases were different for siRNA or U0126, but HeLa cell growth was arrested at the S phase by siRNA and at G1 phase by U0126. A down-regulation in MAPK p42 expression by siRNA and up-regulation by U0126 were noted. The results of real-time quantitative PCR showed that P38 was up-regulated and NUP188 was down-regulated by siRNA in comparison with the control groups, and the results were consistent with those of U0126. Expression levels of STAT1, STAT2, PML and OAS1 induced by siRNA differed from those induced by U0126. siRNA-mediated silencing and deactivation induced by U0126 in MAPK p42 led to growth inhibition in the HeLa cells. The effects of siRNA on HeLa cell growth were different from those of U0126. Dual effects of MAPK p42 siRNA-2 on HeLa cell growth were noted: one consisted of a specific effect induced by siRNA-mediated p42 MAPK silencing and the other exhibited a non-specific interferon-like response.

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Effects of small interfering RNAs targeting MAPK1 on gene expression profile in HeLa cells as revealed by microarray analysis

Cited by 9 publications

References 39 publications

Trisomy 21 consistently activates the interferon response

Trisomy 21 consistently activates the interferon response

Profiling the Human Protein-DNA Interactome Reveals ERK2 as a Transcriptional Repressor of Interferon Signaling

Small-interfering RNA-mediated silencing of the MAPK p42 gene induces dual effects in HeLa cells

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