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Functionally diverse microRNA effector complexes are regulated by extracellular signaling.

ABSTRACT: Because microRNAs (miRNAs) influence the expression of many genes in cells, discovering how the miRNA pathway is regulated is an important area of investigation. We found that the Drosophila miRNA-induced silencing complex (miRISC) exists in multiple forms. A constitutive form, called G-miRISC, is comprised of Ago1, miRNA, and GW182. Two distinct miRISC complexes that lack GW182 are regulated by mitogenic signaling. Exposure of cells to serum, lipids, or the tumor promoter PMA suppressed formation of these complexes. P-miRISC is comprised of Ago1, miRNA, and Loqs-PB, and it associates with mRNAs assembled into polysomes. The other regulated Ago1 complex associates with membranous organelles and is likely an intermediate in miRISC recycling. The formation of these complexes is correlated with a 5- to 10-fold stronger repression of target gene expression inside cells. Taken together, these results indicate that mitogenic signaling regulates the miRNA effector machinery to attenuate its repressive activities.

SUBMITTER: Wu PH

PROVIDER: S-EPMC3797187 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Functionally diverse microRNA effector complexes are regulated by extracellular signaling.

Wu Pei-Hsuan PH Isaji Mamiko M Carthew Richard W RW

Molecular cell 20130919 1

Because microRNAs (miRNAs) influence the expression of many genes in cells, discovering how the miRNA pathway is regulated is an important area of investigation. We found that the Drosophila miRNA-induced silencing complex (miRISC) exists in multiple forms. A constitutive form, called G-miRISC, is comprised of Ago1, miRNA, and GW182. Two distinct miRISC complexes that lack GW182 are regulated by mitogenic signaling. Exposure of cells to serum, lipids, or the tumor promoter PMA suppressed formati ...[more]

PMID: 24055343

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Project description:BackgroundProteins interacting with each other as a complex play an important role in many molecular processes and functions. Directly detecting protein complexes is still costly, whereas many protein-protein interaction (PPI) maps for model organisms are available owing to the fast development of high-throughput PPI detecting techniques. These binary PPI data provides fundamental and abundant information for inferring new protein complexes. However, PPI data from different experiments do not overlap very much usually. The main reason is that the functions of proteins can activate only on certain environment or stimulus. In a short, PPI is condition-specific. Therefore specifying the conditions on when complexes are present is necessary for a deep understanding of their behaviours. Meanwhile, proteins have various interaction ways and control mechanisms to form different kinds of complexes. Thus the discovery of a certain type of complexes should depend on their own distinct biological or topological characteristics. We do not attempt to find all kinds of complexes by using certain features. Here, we integrate transcription regulation data (TR), gene expression data (GE) and protein-protein interaction data at the systems biology level to discover a special kind of protein complex called conditional co-regulated protein complexes. A conditional co-regulated protein complex has three remarkable features: the coding genes of the member proteins share the same transcription factor (TF), under a certain condition the coding genes express co-ordinately and the member proteins interact mutually as a complex to implement a common biological function.ResultsA framework of discovering the conditional co-regulated protein complexes is proposed. Testing on the Yeast data sets under the Cell Cycle, DNA Damage and Dauxic Shift conditions, we identified a total of 29 conditional co-regulated complexes, among which the coding genes in 14 complexes show a strong association with their TFs activity. Based on the close relationship among co-regulation, co-expression and protein-protein interactions in the conditional co-regulated protein complexes, 39 novel TRs were predicted and explained.ConclusionsThis paper was initiated to study conditional co-regulated protein complexes by integrating multiple data sources. Taking into consideration the influence of TFs activity on the protein interactions, we found that the expression coherence of the protein complexes' coding genes changed in accordance to their TFs' activity, which implied that the proteins' interactions also changed in response to the environments. Based on the three features of conditional co-regulated protein complexes, new transcriptional regulation interactions were predicted.

Project description:We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(?5-Cp*)Ir(2-(R'-phenyl)-R-pyridine)Cl] bearing either an electron-donating (-OH, -CH2OH, -CH3) or electron-withdrawing (-F, -CHO, -NO2) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(?5-Cp*)Ir(2-(2'-fluorophenyl)pyridine)Cl] (1) and [(?5-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) exhibit the expected "piano-stool" configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD+. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC50 values ranging from 1 to 89 ?M, with the most potent complex, [(?5-Cp*)Ir(2-(2'-methylphenyl)pyridine)Cl] (13) (A2780 IC50 = 1.18 ?M), being 10× more active than the parent, [(?5-Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(?5-CpxPh)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(?5-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] (2) and [(?5-Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] (4) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems.

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Functionally diverse microRNA effector complexes are regulated by extracellular signaling.

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Functionally diverse microRNA effector complexes are regulated by extracellular signaling.

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