The Conserved microRNA MiR-8 Tunes Atrophin Levels to Prevent Neurodegeneration in Drosophila

Karres, Janina S.; Hilgers, Valérie; Carrera, Inés; Treisman, Jessica E.; Cohen, Stephen M.

doi:10.1016/j.cell.2007.09.020

Cited by 245 publications

(257 citation statements)

References 41 publications

Supporting

Mentioning

242

Contrasting

Unclassified

Order By: Relevance

“…There are many studies that perturb whole-genome expression (Farh et al 2005;Lim et al 2005;Rehwinkel et al 2006;Grimson et al 2007;Karres et al 2007;Linsley et al 2007;Baek et al 2008;Selbach et al 2008). Most of these studies were designed to study the interactions between miRNAs and their targets.…”

Section: Perturbation Of the Expression Level Of Target Vs Nontargetmentioning

confidence: 99%

Evolution under canalization and the dual roles of microRNAs—A hypothesis

Wu¹,

Shen²,

Tang³

2009

Genome Res.

146

160

View full text Add to dashboard Cite

Canalization refers to the process by which phenotypes are stabilized within species. Evolution by natural selection can proceed efficiently only when phenotypes are canalized. The existence and identity of canalizing genes have thus been an important, but controversial topic. Recent evidence has increasingly hinted that microRNAs may be involved in canalizing gene expression. Their paradoxical properties (e.g., strongly conserved but functionally dispensable) suggest unconventional regulatory roles. We synthesized published and unpublished results and hypothesize that miRNAs may have dual functions-in gene expression tuning and in expression buffering. In tuning, miRNAs modify the mean expression level of their targets, but in buffering they merely reduce the variance around a preset mean. In light of the constant emergence of new miRNAs, we further discuss the relative importance of these two functions in evolution.Living organisms process as much information and execute as many instructions as any high-power computers normally do. The difference is that living organisms carry out the tasks under extremely variable environments, whereas no computers are made to withstand even moderate fluctuations in voltage input. Living things must be able to dampen variable inputs (in nutrition, temperature, humidity, genetic background, etc.) to achieve the remarkable stability in the output (development, physiological responses, gene expression, etc.). This phenomenon is the essence of biological homeostasis.Darwin's The Origin of Species (Darwin 1859), on the other hand, is about evolutionary changes. On the surface, evolutionary changes and phenotypic stability may seem like antithetical concepts, but in the language of genetics they are really two sides of the same issue. Evolution by natural selection can proceed only when biological systems are reasonably stable. Imagine a system in which phenotypic manifestation is highly variable. In it natural selection cannot easily distinguish one genotype from another and would have low efficacy. The original nongenetic version of the Darwinian theory encountered many difficulties. One of them was the blending of genetic materials, potentially leading to the homogenization of phenotypes. The other resulted from the ignorance of the difference between genotype and phenotype and the puzzle over the existence of phenotypic variation. Fisher (1930) pointed out that, in Darwin's thinking, phenotypic variation should have been purged by natural selection-only the fittest should have remained.The relationship between evolution and biological homeostasis can best be expressed in quantitative genetic terms. Let V g and V e denote phenotypic variance due to genotypic and environmental effect, respectively. V g 3 e is the interactive term between gene and environment. The total phenotypic variance, V t , can be expressed as follows:For simplicity, we assume no dominance here, but the general principle is the same in more complex systems. Any mechanism of biological homeostasis should redu...

show abstract

Section: Perturbation Of the Expression Level Of Target Vs Nontargetmentioning

confidence: 99%

Evolution under canalization and the dual roles of microRNAs—A hypothesis

Wu¹,

Shen²,

Tang³

2009

Genome Res.

146

160

View full text Add to dashboard Cite

show abstract

“…In addition, a recent study has implicated the loss of miR-146a expression in the progression of hormone-refractory prostate cancer (Lin et al, 2008). Given the ability of microRNAs (miRs) to orchestrate cellular functions by modulating the level of their targeted proteins by either translational arrest or transcript degradation, a capacity often deregulated in cancers by aberrant miR expression (Bartel, 2004;Karres et al, 2007;Ma et al, 2007), we were prompted to evaluate the consequences of miR146a/b expression in human breast cancer cells where constitutive NF-kB activity has been associated with aggressive breast cancer clinical behavior (Zhou et al, 2005).…”

mentioning

confidence: 99%

Expression of microRNA-146 suppresses NF-κB activity with reduction of metastatic potential in breast cancer cells

et al. 2008

View full text Add to dashboard Cite

Cancer cells often acquire a constitutively active nuclear factor-jB (NF-jB) program to promote survival, proliferation and metastatic potential by mechanisms that remain largely unknown. Extending observations from an immunologic setting, we demonstrate that microRNA146a and microRNA-146b (miR-146a/b) when expressed in the highly metastatic human breast cancer cell line MDA-MB-231 function to negatively regulate NF-jB activity. Lentiviral-mediated expression of miR-146a/b significantly downregulated interleukin (IL)-1 receptorassociated kinase and TNF receptor-associated factor 6, two key adaptor/scaffold proteins in the IL-1 and Tolllike receptor signaling pathway, known to positively regulate NF-jB activity. Impaired NF-jB activity was evident from reduced phosphorylation of the NF-jB inhibitor IjBa, reduced NF-jB DNA-binding activity and suppressed expression of the NF-jB target genes IL-8, IL-6 and matrix metalloproteinase-9. Functionally, miR-146a/b-expressing MDA-MB-231 cells showed markedly impaired invasion and migration capacity relative to control cells. These findings implicate miR146a/b as a negative regulator of constitutive NF-jB activity in a breast cancer setting and suggest that modulating miR-146a/b levels has therapeutic potential to suppress breast cancer metastases.

show abstract

“…(49)(50)(51)(52)(53)(54)(55) In several instances, 3 0 UTR of a target gene may carry sites for multiple miRNAs, allowing for combinatorial regulation by these miRNAs. Recently, experimental evidence for the implied cooperativity of miRNAs acting on the same target has been reported.…”

Section: Molecular Basis Of Ip-vementioning

confidence: 99%

“…(70) However, preferential co-expression of target mRNA and miRNA has been experimentally demonstrated in some cases. (51)(52)(53) Since the description of IP-VE implies modulation rather than complete silencing of bi-allelic expression, we consider that for the miRNA to function as a post-transcriptional regulator, co-occurrence with target mRNA is required. Consequently, subtle changes in levels of the co-occurring target genemiRNA pair, under different cellular conditions in different individuals, may lead to variable expressivity.…”

Section: Co-expression Of Mirna and The Target Genementioning

confidence: 99%

Incomplete penetrance and variable expressivity: is there a microRNA connection?

et al. 2009

View full text Add to dashboard Cite

Incomplete penetrance and variable expressivity are non‐Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in fine‐tuning gene expression at translational level, we propose miRNA‐mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3′ UTR, co‐expression of target gene–miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles.

show abstract

The Conserved microRNA MiR-8 Tunes Atrophin Levels to Prevent Neurodegeneration in Drosophila

Cited by 245 publications

References 41 publications

Evolution under canalization and the dual roles of microRNAs—A hypothesis

Evolution under canalization and the dual roles of microRNAs—A hypothesis

Expression of microRNA-146 suppresses NF-κB activity with reduction of metastatic potential in breast cancer cells

Incomplete penetrance and variable expressivity: is there a microRNA connection?

Contact Info

Product

Resources

About