The Complexity of APC/C Regulation Location,Location, Location

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Key Words:

Anaphase Promoting Complex, Cdc27, Kinetochore, Chromosomes, Mitosis     

Location,Location, Location: Compartmentalization of Early Events in Leukotriene Biosynthesis

Leukotrienes (LTs), derived from arachidonic acid (AA) released from the membrane by the action of phospholipase A₂, are potent lipid mediators of the inflammatory response. In 1983, Dahlén et al. demonstrated that LTC₄, LTD₄, and LTE₄ mediate antigen-induced constriction of bronchi in tissue obtained from subjects with asthma (Dahlén, S. E., Hansson, G., Hedqvist, P., Björck, T., Granström, E., and Dahlén, B. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 1712–1716). Over the last 25+ years, substantial progress has been made in understanding how LTs exert their effects, and a broader appreciation for the numerous biological processes they mediate has emerged. LT biosynthesis is initiated by the action of 5-lipoxygenase (5-LOX), which catalyzes the transformation of AA to LTA₄ in a two-step reaction. Ca²⁺ targets 5-LOX to the nuclear membrane, where it co-localizes with the 5-LOX-activating protein FLAP and, when present, the downstream enzyme LTC₄ synthase, both transmembrane proteins. Crystal structures of the AA-metabolizing LOXs, LTC₄ synthase, and FLAP combined with biochemical data provide a framework for understanding how subcellular organizations optimize the biosynthesis of these labile hydrophobic signaling compounds, which must navigate pathways that include both membrane and soluble enzymes. The insights these structures afford and the questions they engender are discussed in this minireview.     

The Importance of Genome Architecture in Cancer Susceptibility: Location,Location, Location

Tumorigenesis requires the interaction between different gene disruptions to convert anormal cell into a cancer cell. These gene disruptions can involve loss of expression ormisexpression of genes through genetic or epigenetic mutations. It is becoming clear that thesedisruptions are not isolated events in the genome, but are affected by genome architecture andthe syntenic relationship of alleles on chromosomes. A better understanding of the genetic andepigenetic changes in cancer is important for the rational design of new therapies. We haverecently shown that background-specific polymorphisms and loci under epigenetic regulationhave a strong effect on cancer susceptibility in a mouse model of astrocytoma. Although thesemice carry mutations in p53 and ras signaling pathways (through mutation of the rasGAPprotein, Nf1), the susceptibility to different tumor types depends strongly on epigeneticregulation and does not show simple Mendelian inheritance. Our results demonstrate theimportance of genome architecture and how tumorigenesis can be accelerated by concomitantloss or gain of multiple genes in a single chromosome rearrangement. Because genomearchitecture is very different between mice and humans, comparing patterns of genomicrearrangement in human cancer and mouse models may help distinguish causal genomic changesfrom correlative changes.     

Location, location, location..

Intra-abdominal fat is an established risk factor for the metabolic syndrome. In this issue of Cell Metabolism, Tran et al. (2008) test the cell-autonomous and location-related properties of transplanted intra-abdominal and subcutaneous fat depots. While subcutaneous fat seems to confer metabolic benefits, species differences in adipose biology justify caution in interpreting the results.     

Regulating TERT: Location,location, location

Comment on: Mechanism of dominant-negative telomerase function.

Binh N. Nguyen, Lynne W. Elmore and Shawn E. Holt. Cell Cycle 2009; 8; In press.     

Location dependent,intragenic recombination in maize

With the use of chromosome interchanges, the waxy (wx) locus on chromosome 9 has been relocated to various positions in the maize genome. Four wx alleles, wx ^C, wx ^B, wx ⁹⁰, and wx ^H21, were crossed to six chromosome translocation stocks (four with break points proximal to wx and, two distal to wx). Of the 26 possible homozygous translocation heteroallelic combinations, the results of eight are available in this report. In most instances, the frequencies of wx intragenic recombination of the rearranged chromosomes were lower than that of the control. A significant difference in degree of reduction in recombination values is found for different heteroallelic combinations at the same location and in one instance for the same heteroallelic combination at a different chromosome position. The linear order of the 4 wx mutants within the wx cistron is wx ^C-wx ^H21-wx ⁹⁰ (wx ^B). Additional effects from both genetic background and seasonal factors of the different plantings also are observed.Journal Paper No. J-6906 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa. Project No. 1335.     

Synthesis of Silk, Mechanism and Location

The location and function of the five or six sets of silk glandsof Araneus diadematus (Cl) are discussed. The structure andfunction of the three major parts of the ampullate gland indicatea synthesizing, collecting, and possibly structuring section.Two methods of stimulation of the ampullate gland, namely emptyingthe gland and cholinergic stimulation, are known. In both casesthere is an initial secretory stage followed by rapid synthesisof new protein. The sequence of events following stimulationby both methods is described, based on studies of the incorporationof labeled protein and RNA precursors and on autoradiographicstudies. Characteristic changes occur in the fine structureduring the stimulatory cycle. Several experiments show thatthe spider has information on the amount of silk available toit for use in web-building. A structure which may act as a biologicaltransducer has been located in the ampullate gland.     

Location,location, location? No. Catalog number

Once you start to read this Editor’s Corner, you might wonder why I have devoted an entire article, albeit a short one, to this topic. Let me assure you there are reasons. First, I want to announce a new policy for the journal that will affect all research papers. Starting with all papers that are not currently in press, we will no longer be asking for geographical locations of research companies that follow the listing of a reagent. In Materials and Methods the authors typically refer to a reagent and then list the company and its location parenthetically. For example, “…p-nitrophenyl phosphate (Sigma-Aldrich, St. Louis, MO).” Instead, we will require catalog numbers. The reason is that it is now quite easy to find a company using the internet, and in fact you rarely need to know the location because it is rare that you would send a written order. On the other hand, knowing the name of the reagent is not always sufficient to narrow down the precise item. For example, if you search for “p-nitrophenyl phosphate” at the Sigma-Aldrich site, you get seven primary choices and it is not at all obvious which one to choose. When my lab uses p-nitrophenyl phosphate for the Pho8?60 assay, we use item N9389, which narrows it down to a precise reagent. Thus, we will start requiring papers to write “…p-nitrophenyl phosphate (Sigma-Aldrich, N9389).

Second, I think this is actually a useful change, and one that many journals will start to institute once they see it being done here. The old style of listing the city and state is a relic that is no longer relevant. Furthermore, it is not even clear in the current global marketplace if this is particularly helpful. For example, if I am ordering an item from Roche Applied Science, why would anyone care where it is coming from? It is highly unlikely that a researcher in Germany or Japan is going to order from Roche Applied Science that happens to be based in Indianapolis, IN when there are much closer sites in Mannheim, Germany and Tokyo, Japan. So, do not be surprised when you start to see more and more journals adopting this approach, and remember that you saw it here first. Autophagy—the cutting edge.