Functional characteristics of a double negative feedback loop mediated by microRNAs

Cai, Shuiming; Zhou, Peipei; Liu, Zengrong

doi:10.1007/s11571-012-9236-7

Cited by 21 publications

(19 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite all the complexities in the network, the model preserves bifurcative characteristics of negative feedback loops as observed elsewhere. 113 These results are consistant with our sensitivity analyses indicating model robustness. Finally, our model predictions regarding tolerance and adaptation were confirmed in 5/7 (>70%) of parameter the parameter sets estimated from random starting points (Fig.…”

Section: Discussionsupporting

confidence: 79%

Computational modeling of cytokine signaling in microglia

et al. 2015

View full text Add to dashboard Cite

Neuroinflammation due to glial activation has been linked to many CNS diseases. We developed a computational model of a microglial cytokine interaction network to study the regulatory mechanisms of microglia-mediated neuroinflammation. We established a literature-based cytokine network, including TNFα, TGFβ, and IL-10, and fitted a mathematical model to published data from LPS-treated microglia. The addition of a previously unreported TGFβ autoregulation loop to our model was required to account for experimental data. Global sensitivity analysis revealed that TGFβ- and IL-10-mediated inhibition of TNFα was critical for regulating network behavior. We assessed the sensitivity of the LPS-induced TNFα response profile to the initial TGFβ and IL-10 levels. The analysis showed two relatively shifted TNFα response profiles within separate domains of initial condition space. Further analysis revealed that TNFα exhibited adaptation to sustained LPS stimulation. We simulated the effects of functionally inhibiting TGFβ and IL-10 on TNFα adaptation. Our analysis showed that TGFβ and IL-10 knockouts (TGFβ KO and IL-10 KO) exert divergent effects on adaptation. TFGβ KO attenuated TNFα adaptation whereas IL-10 KO enhanced TNFα adaptation. We experimentally tested the hypothesis that IL-10 KO enhances TNFα adaptation in murine macrophages and found supporting evidence. These opposing effects could be explained by differential kinetics of negative feedback. Inhibition of IL-10 reduced early negative feedback that results in enhanced TNFα-mediated TGFβ expression. We propose that differential kinetics in parallel negative feedback loops constitute a novel mechanism underlying the complex and non-intuitive pro- versus anti-inflammatory effects of individual cytokine perturbations.

show abstract

Section: Discussionsupporting

confidence: 79%

Computational modeling of cytokine signaling in microglia

et al. 2015

View full text Add to dashboard Cite

show abstract

“…The transcriptional factor N-myc in turn activated RSU1P2 expression and thus formed a positive feedback loop with RSU1P2, which could have strong benefits 48 . In recent years, a miRNA-mediated double-negative feedback loop was proposed to explain how miRNAs could function as a bistable switch without cooperatively binding with transcriptional factors 49 . To evaluate these features in LINC01016, we first predicted binding sites for miR-302a-3p and miR-3130-3p using three bioinformatics software programs (PITA, miRanda and RNAhybid) and verified these results by luciferase assays.…”

Section: Discussionmentioning

confidence: 99%

LINC01016 promotes the malignant phenotype of endometrial cancer cells by regulating the miR-302a-3p/miR-3130-3p/NFYA/SATB1 axis

Pan

Huo

et al. 2018

Cell Death Dis

View full text Add to dashboard Cite

Long noncoding RNAs (lncRNAs) have been implicated in tumorigenesis and cancer progression and are tightly associated with the phenotypes of numerous cancers. However, the functional roles underlying these effects are unknown. The expression levels of LINC01016, miR-302a-3p, miR-3130-3p, NFYA, and SATB1 were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) in 33 endometrial cancer tissues and 20 normal tissues. Bioinformatics analyses, luciferase reporter analyses, chromatin immunoprecipitation (ChIP) assays, and qRT-PCR assays were performed to verify potential binding sites. The qRT-PCR and western blot were used to identify the regulatory mechanisms of LINC01016 in cell biological behavior, which were also examined by cell counting kit -8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU) assays, flow cytometry, wound healing assays, and transwell assays. LINC01016 was substantially upregulated in endometrial cancer tissues, and LINC01016 silencing abolished the malignant behavior of endometrial cancer cells. LINC01016 positively rescued the downstream gene nuclear factor YA (NFYA) by competitively “sponging” miR-302a-3p and miR-3130-3p. In turn, these two miRNAs could inhibit LINC01016 transcription, thus forming two reciprocal repression cycles, which influenced the biological behavior of endometrial cancer cells. MiR-302a-3p and miR-3130-3p could specifically bind with the 3′-UTR regions of NFYA, and NFYA could upregulate the expression of special AT-rich sequence-binding protein 1 (SATB1) as a transcriptional factor. This study was the first to show that the LINC01016–miR-302a-3p/miR-3130-3p/NFYA/SATB1 axis played a crucial role in the occurrence of endometrial cancer. These findings may provide relevant insights into the diagnosis and therapy of endometrial cancer.

show abstract

“…Moreover, NF-κB can inhibit miR146a, which in turn can inhibit the expression of NF-κB through TRAF-6 [ 37 ]. These microRNA-mediated feedback loops are believed to behave as bi-stable switches to regulate downstream processes [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

ANXA1 inhibits miRNA-196a in a negative feedback loop through NF-kB and c-Myc to reduce breast cancer proliferation

et al. 2016

View full text Add to dashboard Cite

MiRNAs are endogenous ~22 nt RNAs which play critical regulatory roles in a wide range of biological and pathological processes, which can act as oncogenes or tumor suppressor genes depending on their target genes. We have recently shown that ANXA1 inhibits the expression of miRNAs including miR196a. Here, we show that miR196a was highly expressed in ER+ MCF-7 breast cancer cells when compared to normal mammary gland cells, with expression levels negatively correlating to ANXA1. ANXA1 inhibits the biogenesis of oncogenic miR-196a by suppressing primary-miR196a indirectly through the stimulation of c-myc and NFkB expression and activity in breast cancer cells. In a negative feedback loop, miR-196a directly inhibits ANXA1 and enhances breast cancer cell proliferation in vitro. Finally, miR196a promotes breast tumor growth in vivo. This study reports a novel regulatory circuit between ANXA1, NF-kB, c-myc and miR-196a which regulates breast cancer cell proliferation and tumor growth.

show abstract

Functional characteristics of a double negative feedback loop mediated by microRNAs

Cited by 21 publications

References 80 publications

Computational modeling of cytokine signaling in microglia

Computational modeling of cytokine signaling in microglia

LINC01016 promotes the malignant phenotype of endometrial cancer cells by regulating the miR-302a-3p/miR-3130-3p/NFYA/SATB1 axis

ANXA1 inhibits miRNA-196a in a negative feedback loop through NF-kB and c-Myc to reduce breast cancer proliferation

Contact Info

Product

Resources

About