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Frank J Slack

Publications and source records attributed to Frank J Slack.

18 recordsLinked to original sources
PubMed2006

microRNA-mediated silencing inside P-bodies.

Cytoplasmic processing bodies, or P-bodies, contain a high concentration of enzymes and factors required for mRNA turnover and translational repression. Recent studies provide evidence that the mRNAs silenced by miRNAs are localized to P-bodies for storage or degradation, perhaps in adjacent subcompartments. mRNP remodeling, potentially induced by miRISC or RNA helicase activity, may cause the modification of the translation initiation complex at the 5' end of mRNA, following translational repression and localization to P-bodies. Further remodeling in P-bodies may facilitate access of the decapping complex to the cap structure, thus inducing mRNA degradation. However, with appropriate signals, stored mRNAs in P-bodies could be released and returned to the translational machinery through mechanisms requiring binding of regulatory proteins to the 3' UTR of mRNAs. Here a model is proposed to explain the repression and degradation stages of the mRNAs within PBs. This model includes preservation or disruption of a stable closed loop structure of the mRNAs, compartmentalization in PBs and mRNA escape triggered by additional binding proteins.

Cell Compartmentation↗
PubMed2006

Micromanagement: a role for microRNAs in mRNA stability.

Small, inhibitory RNA molecules called microRNAs cause large decreases in target protein levels through a post-transcriptional mechanism. Until recently, it was believed this mechanism operated almost exclusively at a step in translation. However, new work has revealed that microRNAs have a second, post-transcriptional mechanism that accelerates the rate of deadenylation, the initial step of mRNA decay.

Animals↗
PubMed2006

MicroRNA control of lifespan and metabolism.

A family of small, noncoding RNAs, known as microRNAs, has recently emerged as sequence-specific regulators of gene expression. Hundreds of microRNAs have been identified in almost all metazoans genomes, but they are only beginning to be classified by functional roles. Here, we review microRNAs that have been shown to play roles in two closely related processes, lifespan and metabolic regulation. Understanding the metabolic and lifespan regulatory roles of these novel gene regulators will undoubtedly further our understanding of the complex genetic networks that control lifespan and metabolism, and will also provide us with novel targets for the therapeutic intervention of metabolic and age-related diseases.

Alleles↗
PubMed2006

Oncomirs - microRNAs with a role in cancer.

MicroRNAs (miRNAs) are an abundant class of small non-protein-coding RNAs that function as negative gene regulators. They regulate diverse biological processes, and bioinformatic data indicates that each miRNA can control hundreds of gene targets, underscoring the potential influence of miRNAs on almost every genetic pathway. Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumour suppressors and oncogenes. miRNAs have been shown to repress the expression of important cancer-related genes and might prove useful in the diagnosis and treatment of cancer.

Animals↗
PubMed2006

MicroRNAs as a potential magic bullet in cancer.

Genes that control cell differentiation and development are frequently mutated in human cancer. Micro (mi)RNAs are small regulatory RNAs that are emerging as important regulators of cell division/differentiation and human cancer genes. In this review, the miRNA cancer connection is discussed and the possibility of using this novel, but potentially powerful new therapy, involving miRNAs, to treat cancers is speculated on. For example, lung cancer is the major cause of cancer deaths in the USA, but existing therapies fail to treat this disease in the overwhelming majority of cases. The let-7 miRNA is one of a number of 'oncomirs', natural miRNA tumor suppressors in lung tissue, which may prove useful in treating lung cancer or enhancing current treatments for lung cancer.

Animals↗
PubMed2005

RAS is regulated by the let-7 microRNA family.

MicroRNAs (miRNAs) are regulatory RNAs found in multicellular eukaryotes, including humans, where they are implicated in cancer. The let-7 miRNA times seam cell terminal differentiation in C. elegans. Here we show that the let-7 family negatively regulates let-60/RAS. Loss of let-60/RAS suppresses let-7, and the let-60/RAS 3'UTR contains multiple let-7 complementary sites (LCSs), restricting reporter gene expression in a let-7-dependent manner. mir-84, a let-7 family member, is largely absent in vulval precursor cell P6.p at the time that let-60/RAS specifies the 1 degrees vulval fate in that cell, and mir-84 overexpression suppresses the multivulva phenotype of activating let-60/RAS mutations. The 3'UTRs of the human RAS genes contain multiple LCSs, allowing let-7 to regulate RAS expression. let-7 expression is lower in lung tumors than in normal lung tissue, while RAS protein is significantly higher in lung tumors, providing a possible mechanism for let-7 in cancer.

3' Untranslated Regions↗
PubMed2005

Temporal and spatial patterning of an organ by a single transcription factor.

During the formation of animal organs, a single regulatory factor can control the majority of cell-fate decisions, but the mechanisms by which this occurs are poorly understood. One such regulator, the nematode transcription factor PHA-4, functions together with various cis-regulatory elements in target genes to regulate spatial and temporal patterning during development of the pharynx.

Animals↗
PubMed2005

Reciprocal expression of lin-41 and the microRNAs let-7 and mir-125 during mouse embryogenesis.

In C. elegans, heterochronic genes control the timing of cell fate determination during development. Two heterochronic genes, let-7 and lin-4, encode microRNAs (miRNAs) that down-regulate a third heterochronic gene lin-41 by binding to complementary sites in its 3'UTR. let-7 and lin-4 are conserved in mammals. Here we report the cloning and sequencing of mammalian lin-41 orthologs. We find that mouse and human lin-41 genes contain predicted conserved complementary sites for let-7 and the lin-4 ortholog, mir-125, in their 3'UTRs. Mouse lin-41 (Mlin-41) is temporally expressed in developing mouse embryos, most dramatically in the limb buds. Mlin-41 is down-regulated during mid-embryogenesis at the time when mouse let-7c and mir-125 RNA levels are up-regulated. Our results suggest that mammalian lin-41 is temporally regulated by miRNAs in order to direct key developmental events such as limb formation.

Amino Acid Sequence↗
PubMed2005

Developmental timing in C. elegans is regulated by kin-20 and tim-1, homologs of core circadian clock genes.

In Caenorhabditis elegans, heterochronic genes constitute a developmental timer that specifies temporal cell fate selection. The heterochronic gene lin-42 is the C. elegans homolog of Drosophila and mammalian period, key regulators of circadian rhythms, which specify changes in behavior and physiology over a 24 hr day/night cycle. We show a role for two other circadian gene homologs, tim-1 and kin-20, in the developmental timer. Along with lin-42, tim-1 and kin-20, the C. elegans homologs of the Drosophila circadian clock genes timeless and doubletime, respectively, are required to maintain late-larval identity and prevent premature expression of adult cell fates. The molecular parallels between circadian and developmental timing pathways suggest the existence of a conserved molecular mechanism that may be used for different types of biological timing.

Animals↗
PubMed2005

The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans.

The let-7 microRNA is phylogenetically conserved and temporally expressed in many animals. C. elegans let-7 controls terminal differentiation in a stem cell-like lineage in the hypodermis, while human let-7 has been implicated in lung cancer. To elucidate let-7's role in temporal control of nematode development, we used sequence analysis and reverse genetics to identify candidate let-7 target genes. We show that the nuclear hormone receptor daf-12 is a let-7 target in seam cells, while the forkhead transcription factor pha-4 is a target in the intestine. Additional likely targets are the zinc finger protein die-1 and the putative chromatin remodeling factor lss-4. Together with the previous identification of the hunchback ortholog hbl-1 as a let-7 target in the ventral nerve cord, our findings show that let-7 acts in at least three tissues to regulate different transcription factors, raising the possibility of let-7 as a master temporal regulator.

Animals↗
PubMed2004

The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3'UTR.

Caenorhabditis elegans let-7, a founding member of the microRNA family, is predicted to bind to six sites in the 3'UTR of the mRNA of its target gene, lin-41, to down-regulate LIN-41. Here, we demonstrate that wild-type let-7 microRNA binds in vitro to RNA from the lin-41 3'UTR. This interaction is dependent on two conserved let-7 complementary sites (LCSs). A 27-nucleotide sequence between the LCSs is also necessary for down-regulation in vivo. LCS mutations compensatory to the lesion in let-7(n2853) can partially restore lin-41 3'UTR function in a let-7(n2853) background, providing the first experimental evidence for an animal miRNA binding directly to its validated target in vivo.

3' Untranslated Regions↗
PubMed2004

Architecture of a validated microRNA::target interaction.

MicroRNAs are small approximately 22 nucleotide regulators of numerous biological processes and bind target gene messenger RNAs to control gene expression. The C. elegans microRNA let-7 and its target lin-41 were the first microRNA::target interaction to be validated in vivo. let-7 molecules form imperfect duplexes with two required let-7 complementary sites in the lin-41 3' UTR. Here, we show that base pairing at both the 5' and 3' ends of the let-7 binding site, as well as the presence of unpaired RNA residues in the predicted duplexes, are required for lin-41 downregulation. In this study, our model for microRNA::target interactions also demonstrates that the context of a microRNA binding can be critical for function, revealing an unforeseen complexity in microRNA::target interactions.

Animals↗
PubMed2003

The time of appearance of the C. elegans let-7 microRNA is transcriptionally controlled utilizing a temporal regulatory element in its promoter.

MicroRNAs (miRNAs) are a large family of small regulatory RNAs that are poorly understood. The let-7 miRNA regulates the timing of the developmental switch from larval to adult cell fates during Caenorhabditis elegans development. Expression of let-7 RNA is temporally regulated, with robust expression in the fourth larval and adult stages. Here, we show that, like let-7 RNA, a transcriptional fusion of the let-7 promoter to gfp is temporally regulated, indicating that let-7 is transcriptionally controlled. Temporal upregulation of let-7 transcription requires an enhancer element, the temporal regulatory element (TRE), situated about 1200 base pairs upstream of the start of the mature let-7 RNA. The TRE is both necessary and sufficient for this temporal upregulation. A TRE binding factor (TREB) is able to bind to the TRE, and a 22-base pair inverted repeat within the TRE is necessary and sufficient for this binding. We also find that the nuclear hormone receptor DAF-12 and the RNA binding protein LIN-28 are both required for the correct timing of let-7 RNA and let-7::gfp expression. We speculate that these heterochronic genes regulate let-7 expression through its TRE.

Animals↗
PubMed2003

The C elegans hunchback homolog, hbl-1, controls temporal patterning and is a probable microRNA target.

hunchback regulates the temporal identity of neuroblasts in Drosophila. Here we show that hbl-1, the C. elegans hunchback ortholog, also controls temporal patterning. Furthermore, hbl-1 is a probable target of microRNA regulation through its 3'UTR. hbl-1 loss-of-function causes the precocious expression of adult seam cell fates. This phenotype is similar to loss-of-function of lin-41, a known target of the let-7 microRNA. Like lin-41 mutations, hbl-1 loss-of-function partially suppresses a let-7 mutation. The hbl-1 3'UTR is both necessary and sufficient to downregulate a reporter gene during development, and the let-7 and lin-4 microRNAs are both required for HBL-1/GFP downregulation. Multiple elements in the hbl-1 3'UTR show complementarity to regulatory microRNAs, suggesting that microRNAs directly control hbl-1. MicroRNAs may likewise function to regulate Drosophila hunchback during temporal patterning of the nervous system.

3' Untranslated Regions↗
PubMed2002

Micro-RNAs: small is plentiful.

Two small temporally regulated RNAs (stRNAs)* of approximately 22 nucleotides regulate timing of gene expression during development of the nematode C. elegans. This regulation occurs at a posttranscriptional, presumably translational, level and is distinct from RNA interference (RNAi). One of the two stRNAs, let-7, as well as its target gene, lin-41, are highly conserved even in humans, suggesting a wide employment of stRNA-mediated gene regulation. Recent reports indicate that these two stRNAs are indeed likely to represent only the tip of an iceberg with hundreds or more of additional micro-RNAs (miRNAs) existing in metazoans. miRNAs might thus be previously underestimated key participants in the field of gene regulation.

Animals↗
PubMed2002

siRNA. A guide for RNA silencing.

RNAi is routinely used to eliminate gene activity for experimental purposes. However, the precise molecular mechanism of RNAi is unknown. Recent papers partially illuminate this mechanism in human cells, advancing the potential application of RNAi toward the treatment of human disease.

Animals↗