《细胞》[Cell]10年9月17日出版pdf全文

scienese

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7 k# z& T$ y" _) K) Q: vLeading Edge
: x& {7 c0 k; _2 p6 r! @In This Issue8 R& ~* u* ?; U" I
APP SHOWS ITS METAL IN ALZHEIMER'S0 o% s  G! ~% Y
PAGE 857
0 G! b  ]% x" k( H+ J" j0 SIron accumulates within neurons in Alzheimer's Disease (AD), whereas zinc accumulates within extraneuronal β-amyloid plaques. Now Duce et al. find that the β-amyloid precursor protein (APP) possesses ferroxidase activity that is specifically inhibited by zinc. In normal cells, APP loads Fe3+ into transferrin and interacts with ferroportin to promote iron export, thus preventing iron accumulation. APP in AD tissue loses ferroxidase activity due to zinc inhibition. These findings provide insight into iron pathology in AD.
2 l6 x- l4 d% F( g" r- `7 F  n  aREPLICATION SEALED WITH A KISS
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Interchromosomal interactions, or chromosome kissing, have been implicated in transcriptional regulation. Now Singh et al. show that such interactions also play a role in replication. The authors show that the S. pombe Reb1 protein forms dimers that bring pairs of Termination sites located on the same or different chromosomes into close proximity to influence fork stalling and site-specific replication termination.
' P. k, a: h# P1 u- mONE SMALL STEP AND ONE GIANT LEAP FOR MYOSIN-VI
3 T8 t! ?% N; z4 E( P0 V0 q. c( YPAGE 879
  f. K5 Z' V5 vMany biological motor molecules move within cells using step sizes predictable from their structures. Myosin-VI, however, has larger and more broadly distributed step sizes than those predicted from its short lever arms. Using high-sensitivity nano-imaging, Nishikawa et al. reveal that this variability is due to two step sizes, one large and one small. The large steps are consistent with a hand-over-hand mechanism, whereas the small steps follow an inchworm-like mechanism and increase in frequency with ADP. Switching between these two mechanisms allows myosin-VI to fulfill its multiple cellular tasks, including vesicle transport and membrane anchoring.) i' ?; F+ A6 Z1 a' S- a* h5 ~. r
BAX TO BAX MEMBRANE FUSION5 [1 e6 I! _) Q) m/ x
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! I+ E9 g$ O* @4 g' HDuring apoptosis, oligomerization of Bax is essential for mitochondrial outer membrane permeabilization and subsequent cytochrome c release. These events are accompanied by mitochondrial fission that requires Drp1, a large GTPase of the dynamin superfamily. Montessuit et al. now report that Drp1 promotes Bid-induced Bax oligomerization by inducing tethering and hemifusion of membranes, independently of its GTPase activity. These findings reveal a new function for Drp1 and provide insight into the mechanism of Bax oligomerization.
+ f  q& u8 t% Y! HTREG RESPONSES TUNED BY MICRORNA
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1 X1 g* Q+ l* r& d# RCD4 T cells differentiate into distinct effector (Th) cell types to protect against infections. Regulatory T (Treg) cells curtail pathology associated with inflammatory responses. Lu et al. now show that in Tregs, activation of Stat1, a key transcription factor downstream of the IFNγ signaling pathway crucial for Th1 differentiation, is regulated by miR-146a and that this restraint enables Treg cell-mediated control of IFNγ-mediated Th1 inflammation. These findings suggest that in a given inflammatory setting, Treg function is dependent upon an optimal range of activation of transcription factors downstream of the cytokine receptors that drive the corresponding type of the immune response.' L1 }! c7 O( {( K) E  C$ Q* k  y" A# P
INFLUENZA HAS ITS OWN BUD-DY SYSTEM
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! N( i( B) z6 e& R0 P) RMany viruses utilize host ESCRT proteins to facilitate their release from the cell. Influenza virus budding, however, is thought to be ESCRT independent. Now Rossman et al. demonstrate that the influenza virus-encoded M2 protein mimics the role of ESCRTs in mediating viral budding and release. The authors identify an essential region within the M2 protein—a highly conserved amphipathic helix—capable of binding the cell membrane and altering its curvature. These data suggest that M2 mediates the final steps of budding for influenza viruses.4 K  U+ }8 \) {' k8 W1 l+ R1 D( [5 \
TRIPPING THE METHYLATION SWITCH IN CANCER
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4 ]  D/ r4 W$ p$ }1 FAlthough genome-wide hypomethylation is a hallmark of many cancers, roles for active DNA demethylation during tumorigenesis are unknown. Rai et al. now show that loss of the APC tumor suppressor gene causes upregulation of a DNA demethylase system and the concomitant hypomethylation of key intestinal cell fate genes. Notably, this hypomethylation maintained zebrafish intestinal cells in an undifferentiated state that was released upon knockdown of demethylase components. Thus, APC controls intestinal cell fate through a switch in DNA methylation dynamics by downregulating demethylase components and thereby promoting methylation of genes essential to commitment to differentiation.
; y; B+ O+ k* W, t( P7 z; a' O" [SETTING CIRCADIAN CLOCKS TO LUNCHTIME1 G, \) n! U) g( w+ C" c* J4 a7 O
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Circadian clocks in peripheral organs are tightly coupled to cellular metabolism and synchronized by feeding-fasting cycles, yet little is known about the molecular mechanisms involved. Here Asher et al. find that the NAD+-dependent ADP-ribosyltransferase activity of PARP-1, an enzyme mainly linked to DNA damage repair, oscillates in a daily manner and is regulated by feeding. PARP-1 binds and poly(ADP-ribosyl)ates CLOCK, a transcriptional regulator of circadian genes, supporting a role for PARP-1 in connecting feeding with the mammalian circadian system.
7 E: p; q) Z1 f0 W/ FTWO HEDGEHOGS FORGE A NEURONAL PATH! q! s% Q. v1 \0 Y8 O' j; S# K- @
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In this issue, Chou et al. reveal two coupled steps in Hedgehog signaling that regulate neuronal patterning. Examining fly olfactory neurons, the authors show that Hedgehog signaling at cell bodies creates populations of neurons with different levels of the Patched receptor. Later, as olfactory axons encounter Hedgehog from the central brain, the level of Patched influences axon target selection. This mechanism contributes to the spatial coordination of olfactory neurons in the periphery with their targets in the brain. Such two-step signaling may represent a general paradigm to organize spatially and temporally segregated developmental events.' q8 Z! s% C" @2 d6 _$ v
EXPANDING READERSHIP FOR ME3
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Trimethyl-lysine modifications on histones are the most stable epigenetic marks, and they control chromatin-mediated gene expression. Vermeulen et al. use mass spectrometry to identify proteins that read trimethylated sites on histones H3 and H4. They go on to analyze the complexes these readers form in cells and identify the sites where the complexes bind throughout the genome. Taken together, these findings provide a landscape showing how recognition of specific modifications is translated into precise biological outcomes like gene activation.
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chendongbo338

好东西

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懵懂干细胞

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