Analysis of microRNA Expression and Function

Wynsberghe, Priscilla M. Van; Chan, Shih-Peng; Slack, Frank J.; Pasquinelli, Amy E.

doi:10.1016/b978-0-12-544172-8.00008-6

Cited by 69 publications

(53 citation statements)

References 81 publications

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“…Increasing evidence shows that many cellular processes, including proliferation, apoptosis, and cytokine release, are regulated by miRNAs that are 19-25 nt in length [45]. Thus, miRNAs have considerable potential to become a research focus for prevention and treatment of IDD, especially for targeting IDD-related cell proliferation and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

MiR-34a promotes Fas-mediated cartilage endplate chondrocyte apoptosis by targeting Bcl-2

Chen

Wang

et al. 2015

Mol Cell Biochem

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Apoptosis of cartilage endplate (CEP) chondrocytes is associated with the pathogenesis of intervertebral disk degeneration (IDD). Recent studies have shown that miR-34a is crucially involved in chondrocyte apoptosis during osteoarthritic cartilage. Here, we investigated the involvement of miR-34a in CEP chondrocyte apoptosis in IDD. In human degenerated CEP chondrocytes, miRNA (miR)-34a was markedly elevated in association with increased apoptosis. Bioinformatics target prediction identified Bcl-2 as a putative target of miR-34a. Furthermore, miR-34a inhibited Bcl-2 expression by directly targeting their 3'-untranslated regions, and this inhibition was abolished by mutation of the miR-34a binding sites. In vitro, knockdown of miR-34a in human endplate chondrocytes resulted in overexpression of Bcl-2, whereas upregulation of miR-34a led to repression of Bcl-2. Fas-mediated apoptosis was decreased when antagonizing miR-34a with locked nucleotide analog-miR-34a in human endplate chondrocytes. Taken together, our results demonstrate that upregulated miR-34a potentiates Fas-mediated endplate chondrocyte apoptosis, which is associated with IDD.

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Section: Discussionmentioning

confidence: 99%

MiR-34a promotes Fas-mediated cartilage endplate chondrocyte apoptosis by targeting Bcl-2

Chen

Wang

et al. 2015

Mol Cell Biochem

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“…miRNAs carry out functions by negatively regulating translation of specific mRNAs. (29) We explored the effects of miR-93 on Sp7. As a result, overexpression of miR-93 only decreased the expression of Sp7 protein but not mRNA, which suggested that miR-93 regulated osteoblast mineralization via suppressing Sp7 at the posttranscriptional level.…”

Section: Discussionmentioning

confidence: 99%

miR-93/Sp7 function loop mediates osteoblast mineralization

Yang

Peng

Chen

et al. 2012

Journal of Bone and Mineral Research

101

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microRNAs (miRNAs) play pivotal roles in osteoblast differentiation. However, the mechanisms of miRNAs regulating osteoblast mineralization still need further investigation. Here, we performed miRNA profiling and identified that miR-93 was the most significantly downregulated miRNA during osteoblast mineralization. Overexpression of miR-93 in cultured primary mouse osteoblasts attenuated osteoblast mineralization. Expression of the Sp7 transcription factor 7 (Sp7, Osterix), a zinc finger transcription factor and critical regulator of osteoblast mineralization, was found to be inversely correlated with miR-93. Then Sp7 was confirmed to be a target of miR-93. Overexpression of miR-93 in cultured osteoblasts reduced Sp7 protein expression without affecting its mRNA level. Luciferase reporter assay showed that miR-93 directly targeted Sp7 by specifically binding to the target coding sequence region (CDS) of Sp7. Experiments such as electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and promoter luciferase reporter assay confirmed that Sp7 bound to the promoter of miR-93. Furthermore, overexpression of Sp7 reduced miR-93 transcription, whereas blocking the expression of Sp7 promoted miR-93 transcription. Our study showed that miR-93 was an important regulator in osteoblast mineralization and miR-93 carried out its function through a novel miR-93/Sp7 regulatory feedback loop. Our findings provide new insights into the roles of miRNAs in osteoblast mineralization. ß

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“…Micro RNAs are short (22 nucleotides) singlestranded RNAs that post-transcriptionally regulate gene expression by binding to imperfect complementary sites within the 3 0 -UTRs of their mRNA targets (Van Wynsberghe et al 2011). In view of our results, it would be worthwhile to explore in future studies if AbOs treatment increases microRNA Let-7d levels in primary hippocampal neurons.…”

Section: Discussionmentioning

confidence: 86%

Sub-lethal levels of amyloid β-peptide oligomers decrease non-transferrin-bound iron uptake and do not potentiate iron toxicity in primary hippocampal neurons

et al. 2012

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Two major lesions are pathological hallmarks in Alzheimer's disease (AD): the presence of neurofibrillary tangles formed by intracellular aggregates of the hyperphosphorylated form of the cytoskeletal tau protein, and of senile plaques composed of extracellular aggregates of amyloid beta (Aβ) peptide. Current hypotheses regard soluble amyloid beta oligomers (AβOs) as pathological causative agents in AD. These aggregates cause significant calcium deregulation and mediate neurotoxicity by disrupting synaptic activity. Additionally, the presence of high concentrations of metal ions such as copper, zinc, aluminum and iron in neurofibrillary tangles and senile plaques, plus the fact that they accelerate the rate of formation of Aβ fibrils and AβOs in vitro, suggests that accumulation of these metals in the brain is relevant to AD pathology. A common cellular response to AβOs and transition metals such as copper and iron is the generation of oxidative stress, with the ensuing damage to cellular components. Using hippocampal neurons in primary culture, we report here the effects of treatment with AβOs on the (+)IRE and (-)IRE mRNA levels of the divalent metal transporter DMT1. We found that non-lethal AβOs concentrations decreased DMT1 (-)IRE without affecting DMT1 (+)IRE mRNA levels, and inhibited non-transferrin bound iron uptake. In addition, since both iron and AβOs induce oxidative damage, we studied whether their neurotoxic effects are synergistic. In the range of concentrations and times used in this study, AβOs did not potentiate iron-induced cell death while iron chelation did not decrease AβOs-induced cell death. The lack of synergism between iron and AβOs suggests that these two neurotoxic agents converge in a common target, which initiates signaling processes that promote neurodegeneration.

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Analysis of microRNA Expression and Function

Cited by 69 publications

References 81 publications

MiR-34a promotes Fas-mediated cartilage endplate chondrocyte apoptosis by targeting Bcl-2

MiR-34a promotes Fas-mediated cartilage endplate chondrocyte apoptosis by targeting Bcl-2

miR-93/Sp7 function loop mediates osteoblast mineralization

Sub-lethal levels of amyloid β-peptide oligomers decrease non-transferrin-bound iron uptake and do not potentiate iron toxicity in primary hippocampal neurons

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