细胞分泌特殊蛋白质应对“生命威胁”

sunsong7

  M( R( g6 V7 O: a. F1 m) d
  |1 W! g% N6 Y. G: S& d

细胞分泌特殊蛋白质应对“生命威胁”

; \) s8 D+ V6 a0 W: O# A% Y

( e6 V& p- _$ v) d

图片来源：Christine Daniloff

) e! R' O6 |/ o5 w. l% c, a9 q# n" i0 ]# e. {8 b5 q* [
当细胞面临“生命威胁”时，它们会快速行动挽救自己。其中一个策略是，它们开始制造能够执行修复DNA等关键任务的蛋白质。美国麻省理工学院（MIT）和阿尔巴尼大学的研究人员如今发现了细胞促进这种蛋白质生产的机制。! r) A. F1 r; k( U
在12月16日的《PLoS遗传学》（PLoS Genetics）上，研究人员报告，当面临压力时，细胞会重组一个复杂的RNA分子化学修饰系统。! |* z3 S4 A6 |9 D: \" q8 A
实验中，研究人员使用4种有毒化学物质（MMS、过氧化氢、砷、漂白剂）处理酵母细胞。借助多元统计分析，研究人员鉴别出了细胞针对不同化学物质展现的不同反应。随后，当敲除某特定蛋白质（其对RNA修复具有重要作用）后，细胞变得更易受有毒化学物质的伤害。5 F- o: _# O9 i0 R6 \/ O. J
论文通讯作者之一、MIT生物工程学教授Peter Dedon说，细胞的这一反应机制可能对压力刺激和荷尔蒙均适用。Dedon目前正在研究细菌如何利用这一机制响应人体白细胞的攻击，或能帮助研究人员开发新的抗生素来对抗这一防御系统。（科学网 梅进/编译）
* ?9 W  ]. \5 y4 m) k0 v: r4 p完成人：彼得•德登课题组/托马斯•贝格利课题组
/ B" A' i: ~" u9 X实验室：MIT生物工程学系  MIT化学系  阿尔巴尼大学生物医学系  MIT环境健康科学中心, b9 l' R( J* g8 v+ i+ T

A Quantitative Systems Approach Reveals Dynamic Control of tRNA Modifications during Cellular Stress

$ H& d* g8 g; p5 VAbstract Top4 e# I# E  g+ f$ r; a$ {% X, m# C
Decades of study have revealed more than 100 ribonucleoside structures incorporated as post-transcriptional modifications mainly in tRNA and rRNA, yet the larger functional dynamics of this conserved system are unclear. To this end, we developed a highly precise mass spectrometric method to quantify tRNA modifications in Saccharomyces cerevisiae. Our approach revealed several novel biosynthetic pathways for RNA modifications and led to the discovery of signature changes in the spectrum of tRNA modifications in the damage response to mechanistically different toxicants. This is illustrated with the RNA modifications Cm, m5C, and m22G, which increase following hydrogen peroxide exposure but decrease or are unaffected by exposure to methylmethane sulfonate, arsenite, and hypochlorite. Cytotoxic hypersensitivity to hydrogen peroxide is conferred by loss of enzymes catalyzing the formation of Cm, m5C, and m22G, which demonstrates that tRNA modifications are critical features of the cellular stress response. The results of our study support a general model of dynamic control of tRNA modifications in cellular response pathways and add to the growing repertoire of mechanisms controlling translational responses in cells.
1 D" |; {0 E8 F" T! O
+ J  S' _1 e' `& I' ?& \Author Summary Top$ F& p% i/ u9 x5 u& t
While the genetic code in DNA is read from four nucleobase structures, there are more than 100 ribonucleoside structures incorporated as post-transcriptional modifications mainly in tRNA and rRNA. These structures and their biosynthetic machinery are highly conserved, with 20–30 present in any one organism, yet the larger biological function of the modifications has eluded understanding. To this end, we developed a sensitive and precise mass spectrometric method to quantify 23 of the 25 ribonucleosides in the model eukaryotic yeast, Saccharomyces cerevisiae. We discovered that the spectrum of ribonucleosides shifts predictably when the cells are exposed to different toxic chemical stimulants, with these signature changes in the spectrum serving as part of the cellular survival response to these exposures. The method also revealed novel enzymatic pathways for the synthesis of several modified ribonucleosides. These results suggest a dynamic reprogramming of the tRNA and rRNA modifications during cellular responses to stimuli, with corresponding modifications working as part of a larger mechanism of translational control during the cellular stress response.
: a$ g+ X0 M! }; a+ X) Whttp://www.plosgenetics.org/arti ... ournal.pgen.1001247

sunsong7

! h; W  A, @9 ?5 }" x

) d$ o# h. O" o5 R& J老狼提示：ES和肿瘤细胞或许也可以通过类似的机制应对“生命威胁”抵御化疗和放疗...

sunsong7

科学家揭示癌细胞躲避化疗机制

' z5 V5 m; U) V! H: P, M
许多癌症患者在经过化疗后，病情会得到缓解，通常能持续数月或数年。但其中的有些案例，癌症最后会复发。而且一旦复发，它们常常会使药物失去效力。2 m: Y# Z8 ^* W7 E
美国麻省理工学院（MIT）的科学家近日通过研究患有淋巴瘤的小鼠发现，少数癌细胞通过躲藏在胸腺中而避开了化疗。在胸腺里，癌细胞“沐浴于”生长因子，从而免受药物的作用。研究领导者、MIT生物学助理教授Michael Hemann说，这些细胞可能就是复发癌症的来源。研究论文10月29日发表于《细胞》。
: l$ f3 r8 ?* E& z研究人员计划不久在小鼠体内开始测试相关药物，这些药物能够干扰其中一种保护因子。研究人员表示，这种药物与传统化疗相结合，形成“组合拳”，可以去除残留癌细胞并防止癌症复发。
! K  C: u& i0 r5 b  aHemann说：“成功的癌症疗法既需要包含杀灭癌细胞的组分，也需要包含阻断促存活信号的组分，而当前的癌症治疗没能标靶这一存活反应。”（科学网 梅进/编译）
6 B3 e2 F; H7 I. h4 d, Z: e0 ]% O
2 S) D6 B& H. o: o5 z6 d

3 d1 ^- _" |$ w

DNA Damage-Mediated Induction of a Chemoresistant Niche

$ k- [2 |# E" Y' ^Luke A. Gilbert1 and Michael T. Hemann1, ,
2 P  H) d8 E% @4 H7 n. M. |$ Q3 s" v1 The Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA 02139, USA! V, d5 p$ i' S8 T
Received 25 November 2009;  revised 31 March 2010;  accepted 24 September 2010.  Published: October 28, 2010.  Available online 28 October 2010.
& J7 _, |5 d: j5 b2 p! o8 V/ N! D
! V" V3 S  c/ e" \8 h0 C) ?3 iSummary5 [/ P, f. d* }8 g7 L
While numerous cell-intrinsic processes are known to play decisive roles in chemotherapeutic response, relatively little is known about the impact of the tumor microenvironment on therapeutic outcome. Here, we use a well-established mouse model of Burkitt's lymphoma to show that paracrine factors in the tumor microenvironment modulate lymphoma cell survival following the administration of genotoxic chemotherapy. Specifically, IL-6 and Timp-1 are released in the thymus in response to DNA damage, creating a “chemo-resistant niche” that promotes the survival of a minimal residual tumor burden and serves as a reservoir for eventual tumor relapse. Notably, IL-6 is released acutely from thymic endothelial cells in a p38-dependent manner following genotoxic stress, and this acute secretory response precedes the gradual induction of senescence in tumor-associated stromal cells. Thus, conventional chemotherapies can induce tumor regression while simultaneously eliciting stress responses that protect subsets of tumor cells in select anatomical locations from drug action.
: G& R# {& @7 Z7 g/ Y) a. }3 @1 b9 ?http://www.sciencedirect.com/sci ... 87&searchtype=a

hylok

回复 sunsong7 的帖子
0 R' T4 ?) m( U/ |# g8 f/ q% l
( A  z8 m) m+ T( r' Y# P人体环境有多复杂，何止胸腺可以让癌细胞躲避？就好像衣服泼上了酱油，早点放水里洗是最好的办法。

hylok

回复 sunsong7 的帖子
9 E0 p0 l  L: i; f0 C- o: q: L0 E8 }+ [
人体中的干细胞多处于休眠状态，就好像乌龟冬眠，代谢少，药物也难以触及，而癌症细胞大多处于高速分裂状态，这是放、化疗治疗的切入点。细胞在分裂的时候最脆弱，最容易破坏。也许有部分癌细胞可能阶段性休眠躲避了化疗，但是我倾向于认为异质化是癌细胞躲避化疗的主要手段。

sunsong7

科学家揭示刚地弓形虫入侵细胞机制

) Y& S* v: F8 ]' x8 j 4 T1 Y* L3 `& x) P/ q  _
刚地弓形虫和其他寄生虫采用特定蛋白，阻止宿主中免疫蛋白破坏在自身周围包裹的保护膜，从而使自己不被宿主细胞杀死。（图片来源：Wandy Beatty）  1 _3 G3 B& O, I: C
8 \( v7 y" B) F$ _+ \. o, q
美国华盛顿大学医学院的研究人员近日通过研究，找到为何ROP18蛋白可让寄生虫中的危险种类——刚地弓形虫（Toxoplasma gondii）存活于宿主细胞的原因。这项发现将进一步有助于找到对抗弓形虫以及其他寄生虫的方法。研究报告刊登在近期的《细胞—宿主与微生物》上。! A* z  c8 u5 A0 z
6 w6 P7 s- D7 W& j
据流行病学家估计，人类每四个人中就有一人感染弓形虫，但通常只有免疫系统差的人才会因为感染弓形虫而患上很严重的疾病。不过个别情况下，免疫系统正常的人也有可能因此患上严重的眼部疾病或中枢神经系统疾病，并造成女性所怀胎儿的先天性缺陷或死亡。) `% q; R' K- P- f" D. g0 x
1 _  t# p! {+ F- H% {9 P
在这项最新研究中，科学家们发现当弓形虫进入宿主细胞时，会生成一层保护膜包裹自身，使自己受细胞环境影响而不被杀死，ROP180的作用则是让宿主细胞某些蛋白失效而无法破坏这层保护膜。
' X. R& g( M. L1 Y8 E, f1 n
# X0 J3 B8 L5 D' T3 A) {  |6 t“如果我们能找到方法阻止ROP18以及寄生虫的其他蛋白，那么宿主细胞将在抗感染过程中占有优势。”论文第一作者Sarah Fentress表示。
7 _, {  |$ p+ ?, N: \ ' O7 X' i* w- W2 }, X! s
研究人员进一步研究发现，ROP18的作用机制是通过和宿主细胞中一类与免疫有关的鸟苷酸酶（GTPase）相结合，使得后者失效，进而无法破坏弓形虫周围的保护膜。
9 q* ~( R; c0 y" f8 G6 @; N 0 g; j' m4 p3 z; S- y' [
“但也有例外，因为每个人的免疫鸟苷酸酶种类是不一样的，”Fentress特别指出，“有这么一组类似的免疫识别蛋白，我们称其为鸟苷酸结合蛋白。现阶段我们正用这种蛋白来进行测试，看ROP180是否也能用类似方式让其失效”。
# C! k1 n9 i( G; t) M
6 e6 R: a6 ]- h2 _! D0 C7 X# E此外，导致疟疾产生的疟原虫和弓形虫属同族寄生虫，其入侵宿主细胞时同样利用了保护膜。“疟原虫会分泌FIKK蛋白，而不是ROP18”，Fentress说，“它很有可能也是通过让鸟苷酸酶或鸟苷酸酶结合蛋白失效而破坏细胞防御机制的”。（科学网 张笑/编译）# @8 ~' L. j  H3 L# K" `) j  D$ H

; O# C. s/ P% |5 ]/ x' \, }相关仪器：液质联用仪  QSTAR XL基质辅助激光解吸附电离-四极离子阱-飞行时间质谱仪（MALDI-QTOF-MS）  ECL Plus蛋白印迹系统  FLA5000磷光分析仪
" ^6 _8 j9 `; F& M( h 5 N: O# B  |5 n; P
完成人：大卫·西布利课题组
5 X* g1 M- J4 t3 F

Phosphorylation of Immunity-Related GTPases by a Toxoplasma gondii-Secreted Kinase Promotes Macrophage Survival and Virulence

( g% N* ^( B% LAuthors   Sarah J. Fentress, Michael S. Behnke, Ildiko R. Dunay, Mona Mashayekhi, Leah M. Rommereim, Barbara A. Fox, David J. Bzik, Gregory A. Taylor, Benjamin E. Turk, Cheryl F. Lichti, R. Reid Townsend, Wei Qiu, Raymond Hui, Wandy L. Beatty, L. David Sibley, x( T1 f  G  d: c* w( s. J
Highlights+ w& W4 D. Q: B& R
•The secreted Toxoplasma gondii kinase ROP18 protects parasites from macrophage killing : O. O7 {$ P$ _" p, ^5 f
•The host factor Irgb6 is required for efficient parasite killing by macrophages . U# H  N' ~2 l, H* N0 L  {* D
•ROP18 phosphorylates IRG family members within a conserved domain 4 W7 m( g- A: r$ l9 \
•ROP18 is necessary and sufficient to block IRG vacuolar accumulation0 |4 o% V( V6 _

5 h  _* ?/ m4 T  oSummary
9 q) K0 l1 @& VMacrophages are specialized to detect and destroy intracellular microbes and yet a number of pathogens have evolved to exploit this hostile niche. Here we demonstrate that the obligate intracellular parasite Toxoplasma gondii disarms macrophage innate clearance mechanisms by secreting a serine threonine kinase called ROP18, which binds to and phosphorylates immunity-related GTPases (IRGs). Substrate profiling of ROP18 revealed a preference for a conserved motif within switch region I of the GTPase domain, a modification predicted to disrupt IRG function. Consistent with this, expression of ROP18 was both necessary and sufficient to block recruitment of Irgb6, which was in turn required for parasite destruction. ROP18 phosphorylation of IRGs prevented clearance within inflammatory monocytes and IFN-γ-activated macrophages, conferring parasite survival in vivo and promoting virulence. IRGs are implicated in clearance of a variety of intracellular pathogens, suggesting that other virulence factors may similarly thwart this innate cellular defense mechanism.9 |) u( ~* q1 E' c8 f9 m6 n: }7 f
http://www.cell.com/cell-host-mi ... i/S1931312810003781