Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.
MicroRNAs are small 19 to 22 nucleotide sequences of RNA that participate in the regulation of cell differentiation, cell cycle progression, and apoptosis. MicroRNAs act much like small interfering RNA, annealing with RISC, to cleave messenger RNA, and microRNAs exert translational inhibition that is incompletely understood. They are important factors in tumorigenesis and have been the subject of research in many types of cancers, including colon cancer. MicroRNAs may be abnormally down-regulated or up-regulated in colon-cancer tissue. Artificial dysregulation of certain microRNAs will trigger tumorigenesis or apoptosis depending on which microRNA is manipulated. Although the natural mechanisms for the dysregulation of microRNAs is still largely unknown, one theory tested in colon cancers proposes that DNA hypermethylation leads to down-regulation of certain microRNAs. Specific microRNA expression patterns help characterize specific cancers and may be used as a prognostication factor and in following patient response to 5-fluorouracil chemotherapy. This article reviews the existing literature pertaining to the study of microRNA in colorectal cancer.
SUMMARY To test the directness of factors in initiating PIWI-directed gene silencing, we employed a Piwi-interacting RNA (piRNA)-targeted reporter assay in Drosophila OSS cells [1]. This assay confirmed direct silencing roles for piRNA biogenesis factors and PIWI-associated factors [2–12], but suggested that chromatin-modifying proteins may act downstream of the initial silencing event. Our data also revealed that RNA Polymerase II associated proteins like PAF1 and RTF1 antagonizes PIWI-directed silencing. PAF1 knockdown enhances PIWI silencing of reporters when piRNAs target the transcript region proximal to the promoter. Loss of PAF1 suppresses endogenous transposable element (TE) transcript maturation, whereas a subset of gene transcripts and long-non-coding RNAs adjacent to TE insertions are affected by PAF1 knockdown in a similar fashion to piRNA-targeted reporters. Additionally, transcription activation at specific TEs and TE-adjacent loci during PIWI knockdown is suppressed when PIWI and PAF1 levels are both reduced. Our study suggests a mechanistic conservation between fission yeast PAF1 repressing AGO1/siRNA-directed silencing [13, 14] and Drosophila PAF1 opposing PIWI/piRNA-directed silencing.
A large portion of the Drosophila melanogaster genome is contained within heterochromatic regions of chromosomes, predominantly at centromeres and telomeres. The remaining euchromatic portions of the genome have been extensively characterized with respect to gene organization, function and regulation. However, it has been difficult to derive similar data for sequences within centromeric (centric) heterochromatin because these regions have not been as amenable to analysis by standard genetic and molecular tools. Here we present an updated genetic and molecular analysis of chromosome 3L centric heterochromatin (3L Het). We have generated and characterized a number of new, overlapping deficiencies (Dfs) which remove regions of 3L Het. These Dfs were critically important reagents in our subsequent genetic analysis for the isolation and characterization of lethal point mutations in the region. The assignment of these mutations to genetically-defined essential loci was followed by matching them to gene models derived from genome sequence data: this was done by using molecular mapping plus sequence analysis of mutant alleles, thereby aligning genetic and physical maps of the region. We also identified putative essential gene sequences in 3L Het by using RNA interference to target candidate gene sequences. We report that at least 25, or just under 2/3 of loci in 3L Het, are essential for viability and/or fertility. This work contributes to the functional annotation of centric heterochromatin in Drosophila , and the genetic and molecular tools generated should help to provide important insights into the organization and functions of gene sequences in 3L Het.
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