Oncogenic c-Myc has been described to modulate the expression of a subset of microRNAs (miRNAs), which include miR-22; however, the mechanism through which a miRNA controls c-Myc activity remains unclear. Here we report a novel anti-c-Myc function mediated by miR-22. Ectopically expressed miR-22 inhibited cell proliferation and anchorage-independent growth of human cancer cell lines. Microarray screening and western analyses revealed that miR-22 repressed the c-Mycbinding protein MYCBP, a positive regulator of c-Myc. Consistent with this, reporter assays showed that miR-22-mediated MYCBP gene suppression largely depends on the conserved miR-22 target site within the MYCBP 3 0 -untranslational region (3 0 UTR), implying that MYCBP mRNA is a direct miR-22 target. Depletion of MYCBP using small interfering RNA (siRNA) recapitulated the miR-22-induced anti-growth effect on tumor cells, whereas ectopically expressed MYCBP rescued cells from the growth suppression mediated by miR-22. Moreover, repression of MYCBP by miR-22 downregulated a panel of E-box-containing c-Myc target genes. Our results suggest that miR-22 acts as a tumor suppressor through direct repression of MYCBP expression and subsequent reduction of oncogenic c-Myc activities. As c-Myc inhibits the expression of miR-22, we propose a novel positive feedback loop formed by oncogenic c-Myc to accelerate cell proliferation by suppressing miR-22, a potent inhibitor of MYCBP.
Climate warming affects soil carbon (C) dynamics, with possible serious consequences for soil C stocks and atmospheric CO2 concentrations. However, the mechanisms underlying changes in soil C storage are not well understood, hampering long‐term predictions of climate C‐feedbacks. The activity of the extracellular enzymes ligninase and cellulase can be used to track changes in the predominant C sources of soil microbes and can thus provide mechanistic insights into soil C loss pathways. Here we show, using meta‐analysis, that reductions in soil C stocks with warming are associated with increased ratios of ligninase to cellulase activity. Furthermore, whereas long‐term (≥5 years) warming reduced the soil recalcitrant C pool by 14%, short‐term warming had no significant effect. Together, these results suggest that warming stimulates microbial utilization of recalcitrant C pools, possibly exacerbating long‐term climate‐C feedbacks.
Vacuolar protein sorting protein 29 (Vps29p), which is involved in retrograde trafficking from prevacuolar endosomes to the trans-Golgi network, performs its biological functions by participating in the formation of a "retromer complex." In human cells, this complex comprises four conserved proteins: hVps35p, hVps29p, hVps26p, and sorting nexin 1 protein (SNX1). Here, we report the crystal structure of hVps29p at 2.1 Å resolution, the first three-dimensional structure of the retromer subunits. This novel structure adopts a four-layered ␣---␣ sandwich fold. hVps29p contains a metal-binding site that is very similar to the active sites of some proteins of the phosphodiesterase/nuclease protein family, indicating that hVps29p may carry out chemically similar functions. Structure and sequence conservation analysis suggests that hVps29p contains two proteinprotein interaction sites. One site, which potentially serves as the interface between hVps29p and hVps35p, comprises 5 conserved hydrophobic and 8 hydrophilic residues. The other site is relatively more hydrophilic and may serve as a binding interface with hVps26p, SNX1, or other target proteins.To function properly for the organelles in eukaryotic cells, it is necessary that specific sets of proteins and lipids are sorted and delivered to various intracellular compartments efficiently. The trafficking of proteins and lipids between intracellular organelles requires a series of proteins that are involved in the membrane transport pathways (1-3). Genetic screens in yeast have uncovered more than 50 Vps 1 genes. The products of these Vps genes are involved directly or indirectly in protein sorting or trafficking between the late Golgi and the vacuoles (4 -6). Disruption of Vps genes can cause disturbance and missorting of many proteins, such as CPY. As a vacuolar hydrolase, CPY is recognized by Vps10p in the late Golgi. Vps10p binds to CPY and conveys it via vesicle to the prevacuolar compartment where Vps10p releases it. After that, Vps10p returns to the Golgi for further rounds of transportation. Some yeast Vps gene products, Vps26p, Vps29p, Vps35p, Vps5p, and Vps17p, are necessary for the retrograde retrieval process of Vps10p from endosomes back to the trans-Golgi network (7-10). By forming a complex named "retromer complex," the five proteins are also involved in the proper sorting and transportation of dipetidyl aminopeptidase A, Kex2 protease (Kex2p), polymeric immunoglobulin receptor, and mannose 6-phosphate receptor (9 -12). This complex consists of two subcomplexes. One subcomplex, consisting of Vps35p, Vps29p, and Vps26p, is responsible for selecting cargoes retrieved from the prevacuolar compartment (10, 13). The other subcomplex of Vps5p and Vps17p provides structural components to complete the retromer complex and mechanical force for vesicle budding (10,14,15). The retromer complex is conserved and has homologs in mammalian cells. In human cells, the retromer complex comprises hVps26p, hVps29p, hVps35p, and SNX1 (the mammalian homolog of Vps5p) (16,...
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