Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates ...both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the nonautophagy Vps34 complex by phosphorylating T163/S165 in Vps34 and therefore suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the proautophagy Vps34 complex by phosphorylating S91/S94 in Beclin1 to induce autophagy. Atg14L, an autophagy-essential gene present only in the proautophagy Vps34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK in nutrient stress response and autophagy.
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► Different Vps34 complexes are distinctly regulated upon energy stress ► AMPK activates the proautophagy Vps34 complex by phosphorylating Beclin1 ► AMPK inhibits the nonautophagic Vps34 complex by phosphorylating Vps34 ► ATG14L determines whether the Vps34 complex is activated or inhibited by AMPK
Atg14 acts as a molecular switch to modulate the outcome of AMPK phosphorylation of Vps34 complexes during nutrient stress signaling. Atg14 suppresses Vps34 phosphorylation, and thus vesicle trafficking, while stimulating Beclin phosphorylation and autophagy.
Origins of tumor-associated macrophages and neutrophils Cortez-Retamozo, Virna; Etzrodt, Martin; Newton, Andita ...
Proceedings of the National Academy of Sciences - PNAS,
02/2012, Letnik:
109, Številka:
7
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Tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) can control cancer growth and exist in almost all solid neoplasms. The cells are known to descend from immature monocytic ...and granulocytic cells, respectively, which are produced in the bone marrow. However, the spleen is also a recently identified reservoir of monocytes, which can play a significant role in the inflammatory response that follows acute injury. Here, we evaluated the role of the splenic reservoir in a genetic mouse model of lung adenocarcinoma driven by activation of oncogenic Kras and inactivation of p53. We found that high numbers of TAM and TAN precursors physically relocated from the spleen to the tumor stroma, and that recruitment of tumor-promoting spleen-derived TAMs required signaling of the chemokine receptor CCR2. Also, removal of the spleen, either before or after tumor initiation, reduced TAM and TAN responses significantly and delayed tumor growth. The mechanism by which the spleen was able to maintain its reservoir capacity throughout tumor progression involved, in part, local accumulation in the splenic red pulp of typically rare extramedullary hematopoietic stem and progenitor cells, notably granulocyte and macrophage progenitors, which produced CD11b+ Ly-6Chi monocytic and CD11b+ Ly-6Ghi granulocytic cells locally. Splenic granulocyte and macrophage progenitors and their descendants were likewise identified in clinical specimens. The present study sheds light on the origins of TAMs and TANs, and positions the spleen as an important extramedullary site, which can continuously supply growing tumors with these cells.
Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to ...identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.
We present Reactive Vega, a system architecture that provides the first robust and comprehensive treatment of declarative visual and interaction design for data visualization. Starting from a single ...declarative specification, Reactive Vega constructs a dataflow graph in which input data, scene graph elements, and interaction events are all treated as first-class streaming data sources. To support expressive interactive visualizations that may involve time-varying scalar, relational, or hierarchical data, Reactive Vega's dataflow graph can dynamically re-write itself at runtime by extending or pruning branches in a data-driven fashion. We discuss both compile- and run-time optimizations applied within Reactive Vega, and share the results of benchmark studies that indicate superior interactive performance to both D3 and the original, non-reactive Vega system.
Abstract Platelet-rich plasma (PRP) has been the subject of hundreds of publications in recent years. Reports of its effects in tissue, both positive and negative, have generated great interest in ...the orthopaedic community. Protocols for PRP preparation vary widely between authors and are often not well documented in the literature, making results difficult to compare or replicate. A classification system is needed to more accurately compare protocols and results and effectively group studies together for meta-analysis. Although some classification systems have been proposed, no single system takes into account the multitude of variables that determine the efficacy of PRP. In this article we propose a simple method for organizing and comparing results in the literature. The PAW classification system is based on 3 components: (1) the absolute number of Platelets, (2) the manner in which platelet Activation occurs, and (3) the presence or absence of White cells. By analyzing these 3 variables, we are able to accurately compare publications.
The ability of cells to respond to changes in nutrient availability is essential for the maintenance of metabolic ho- meostasis and viability. One of the key cellular responses to nutrient withdrawal ...is the upregulation of autophagy. Recently, there has been a rapid expansion in our knowledge of the molecular mechanisms involved in the regula- tion of mammalian autophagy induction in response to depletion of key nutrients. Intracellular amino acids, ATP, and oxygen levels are intimately tied to the cellular balance of anabolic and catabolic processes. Signaling from key nutrient-sensitive kinases mTORC1 and AMP-activated protein kinase （AMPK） is essential for the nutrient sensing of the autophagy pathway. Recent advances have shown that the nutrient status of the cell is largely passed on to the autophagic machinery through the coordinated regulation of the ULK and VPS34 kinase complexes. Identification of extensive crosstalk and feedback loops converging on the regulation of ULK and VPS34 can be attributed to the im- portance of these kinases in autophagy induction and maintaining cellular homeostasis.
Autophagy is the primary catabolic program of the cell that promotes survival in response to metabolic stress. It is tightly regulated by a suite of kinases responsive to nutrient status, including ...mammalian target of rapamycin complex 1 (mTORC1), AMP-activated protein kinase (AMPK), protein kinase C-α (PKCα), MAPK-activated protein kinases 2/3 (MAPKAPK2/3), Rho kinase 1 (ROCK1), c-Jun N-terminal kinase 1 (JNK), and Casein kinase 2 (CSNK2). Here, we highlight recently uncovered mechanisms linking amino acid, glucose, and oxygen levels to autophagy regulation through mTORC1 and AMPK. In addition, we describe new pathways governing the autophagic machinery, including the Unc-51-like (ULK1), vacuolar protein sorting 34 (VPS34), and autophagy related 16 like 1 (ATG16L1) enzyme complexes. Novel downstream targets of ULK1 protein kinase are also discussed, such as the ATG16L1 subunit of the microtubule-associated protein 1 light chain 3 (LC3)-lipidating enzyme and the ATG14 subunit of the VPS34 complex. Collectively, we describe the complexities of the autophagy pathway and its role in maintaining cellular nutrient homeostasis during times of starvation.
Autophagy is the primary degradative program of the cell that provides essential macromolecular building blocks to fuel biosynthetic pathways during times of nutrient deprivation.Recruitment of the LC3-lipidating enzyme to maturing autophagosomes is regulated by both VPS34-mediated phospholipid production and the ULK1 complex.Changes in amino acid, glucose, and oxygen levels are sensed by stress-sensitive kinases mTORC1 and AMPK and control autophagy through distinct but strikingly similar downstream targets.Recent advances revealed new pathways regulating the stability and activity of the core autophagic machinery in response to nutrient status, including the ULK1, VPS34, and ATG16L1 enzyme complexes.The most upstream enzyme in the autophagy pathway, ULK1 protein kinase, directly phosphorylates several autophagy proteins under starvation, including the VPS34 and ATG16L1 complexes, to promote autophagy.
Translocation events are frequent in cancer and may create chimeric fusions or 'regulatory rearrangements' that drive oncogene overexpression. Here we identify super-enhancer translocations that ...drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole-genome sequencing data and chromatin maps highlight distinct chromosomal rearrangements that juxtapose super-enhancers to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers interact with the MYB promoter. Remarkably, MYB protein binds to the translocated enhancers, creating a positive feedback loop that sustains its expression. MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells. Bromodomain inhibitors slow tumor growth in ACC primagraft models in vivo. Thus, our study identifies super-enhancer translocations that drive MYB expression and provides insight into downstream MYB functions in alternate ACC lineages.
ABSTRACT We present a robust measurement and analysis of the rest-frame ultraviolet (UV) luminosity functions at z = 4-8. We use deep Hubble Space Telescope imaging over the Cosmic Assembly ...Near-infrared Deep Extragalactic Legacy Survey/GOODS fields, the Hubble Ultra Deep Field, and the Hubble Frontier Field deep parallel observations near the Abell 2744 and MACS J0416.1-2403 clusters. The combination of these surveys provides an effective volume of 0.6-1.2 × 106 Mpc3 over this epoch, allowing us to perform a robust search for faint 18) and bright (M 21) high-redshift galaxies. We select candidate galaxies using a well-tested photometric redshift technique with careful screening of contaminants, finding a sample of 7446 candidate galaxies at 3.5 8.5, with >1000 galaxies at 6-8. We measure both a stepwise luminosity function for candidate galaxies in our redshift samples, and a Schechter function, using a Markov Chain Monte Carlo analysis to measure robust uncertainties. At the faint end, our UV luminosity functions agree with previous studies, yet we find a higher abundance of UV-bright candidate galaxies at 6. Our best-fit value of the characteristic magnitude is consistent with −21 at 5, which is different than that inferred based on previous trends at lower redshift, and brighter at ∼2 significance than previous measures at z = 6 and 7. At z = 8, a single power law provides an equally good fit to the UV luminosity function, while at z = 6 and 7 an exponential cutoff at the bright end is moderately preferred. We compare our luminosity functions to semi-analytical models, and find that the lack of evolution in is consistent with models where the impact of dust attenuation on the bright end of the luminosity function decreases at higher redshift, although a decreasing impact of feedback may also be possible. We measure the evolution of the cosmic star-formation rate (SFR) density by integrating our observed luminosity functions to , correcting for dust attenuation, and find that the SFR density declines proportionally to (1 ) at 4, which is consistent with observations at 9. Our observed luminosity functions are consistent with a reionization history that starts at 10, completes at 6, and reaches a midpoint (x 0.5) at 6.7 9.4. Finally, using a constant cumulative number density selection and an empirically derived rising star-formation history, our observations predict that the abundance of bright z = 9 galaxies is likely higher than previous constraints, although consistent with recent estimates of bright 10 galaxies.
The determination of final organ size is a highly coordinated and complex process that relies on the precise regulation of cell number and/or cell size. Perturbation of organ size control contributes ...to many human diseases, including hypertrophy, degenerative diseases, and cancer. Hippo and TOR are among the key signaling pathways involved in the regulation of organ size through their respective functions in the regulation of cell number and cell size. Here, we review the general mechanisms that regulate organ growth, describe how Hippo and TOR control key aspects of growth, and discuss recent findings that highlight a possible coordination between Hippo and TOR in organ size regulation.
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