methods-to-classify-cytoplasmic-foci-as-mammalian-stress-granules

Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules

Cells are often challenged by sudden environmental changes. Stress Granules (SGs), cytoplasmic ribonucleoprotein complexes that form in cells exposed to ...

Brigham and Women's Hospital

Harvard Medical School

&#x7A0B;&#x5E8F;&#x6027;&#x7684;&#x7EC6;&#x80DE;&#x6B7B;&#x4EA1; 4 (PDCD4) &#x88AB;&#x79F0;&#x4E3A;&#x6291;&#x764C;&#x9AD8;&#x8868;&#x8FBE;&#x66F4;&#x597D;&#x7684;&#x7ED3;&#x679C;&#xFF0C;&#x5728;&#x8BB8;&#x591A;&#x764C;&#x75C7;&#x7C7B;&#x578B;&#x5173;&#x8054;&#x3002;&#x5C1A;&#x672A;&#x5927;&#x91CF;&#x9AD8; PDCD4 &#x5BF9;&#x80BF;&#x7624;&#x764C;&#x75C7;&#x60A3;&#x8005;&#x6709;&#x4E0D;&#x826F;&#x7684;&#x5B58;&#x6D3B;&#x7387;&#xFF0C;&#x6697;&#x793A;&#x7624;&#x9014;&#x5F84;&#x53EF;&#x80FD;&#x6291;&#x5236;&#x6216;&#x66F4;&#x6539; PDCD4 &#x51FD;&#x6570;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x63A2;&#x8BA8;&#x7684;&#x610F;&#x4E49;&#x5728; PDCD4 &#x4E73;&#x817A;&#x764C;&#x548C;&#x6807;&#x8BC6;&#x7CBE;&#x6C28;&#x9178;&#x7532;&#x57FA;&#x8F6C;&#x79FB;&#x9176;&#x86CB;&#x767D; 5 (PRMT5) &#x4E3A;&#x4ECE;&#x6839;&#x672C;&#x4E0A;&#x6539;&#x53D8; PDCD4 &#x529F;&#x80FD;&#x7684;&#x8F85;&#x9176;&#x3002;&#x5177;&#x4F53;&#x800C;&#x8A00;&#xFF0C;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#xFF0C;&#x5171; PDCD4 &#x7684;&#x8868;&#x8FBE;&#x548C; PRMT5 &#x5728;&#x4E73;&#x817A;&#x764C;&#x539F;&#x4F4D;&#x6A21;&#x578B;&#x4F1A;&#x5BFC;&#x81F4;&#x52A0;&#x901F;&#x7684;&#x80BF;&#x7624;&#x7684;&#x751F;&#x957F;&#x548C;&#x6B64;&#x589E;&#x957F;&#x8868;&#x578B;&#x662F;&#x4F9D;&#x8D56;&#x4E8E; PRMT5 &#x7684;&#x50AC;&#x5316;&#x6D3B;&#x6027;&#x548C; N &#x672B;&#x7AEF;&#x533A;&#x57DF;&#x5185;&#x7684;&#x7532;&#x57FA;&#x5316; PDCD4 &#x7684;&#x7F51;&#x7AD9;&#x3002;&#x4E0E;&#x5F02;&#x79CD;&#x79FB;&#x690D;&#x6A21;&#x578B;&#x4E2D;&#xFF0C;&#x53D1;&#x73B0;&#x662F;&#x9AD8;&#x67B6;&#x7684; PDCD4 &#x8868;&#x8FBE;&#x5F0F;&#x5173;&#x8054;&#x4E0E;&#x4E73;&#x817A;&#x764C;&#x60A3;&#x8005;&#x7684;&#x80BF;&#x7624;&#x5305;&#x542B;&#x66F4;&#x9AD8;&#x6C34;&#x5E73;&#x7684; PRMT5 &#x961F;&#x5217;&#x5185;&#x66F4;&#x7CDF;&#x7CD5;&#x7684;&#x7ED3;&#x679C;&#x3002;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x4E3A;&#x6539;&#x53D8;&#x5176;&#x80BF;&#x7624;&#x6291;&#x5236;&#x529F;&#x80FD;&#x548C;&#x6307;&#x5411;&#x8BE5;&#x5B9E;&#x7528;&#x7A0B;&#x5E8F;&#x7684; PDCD4/PRMT5 &#x72B6;&#x6001;&#x4F5C;&#x4E3A;&#x9884;&#x540E;&#x751F;&#x7269;&#x6807;&#x8BB0;&#x7269;&#x548C;&#x5316;&#x7597;&#x7684;&#x6F5C;&#x5728;&#x76EE;&#x6807;&#x7684; PDCD4 &#x5C55;&#x73B0;&#x65B0;&#x7684;&#x8F85;&#x9176;&#x3002;

&#x7CBE;&#x6C28;&#x9178;&#x7532;&#x57FA;&#x8F6C;&#x79FB;&#x9176;&#x86CB;&#x767D; 5 &#x7CBE;&#x6C28;&#x9178;&#x7532;&#x57FA;&#x5316;&#x80BF;&#x7624;&#x6291;&#x764C;&#x7F16;&#x7A0B;&#x7EC6;&#x80DE;&#x6B7B;&#x4EA1; 4 &#x52A0;&#x901F;&#x80BF;&#x7624;&#x7684;&#x751F;&#x957F;&#x3002;

Programmed cell death 4 (PDCD4) has been described as a tumor suppressor, with high expression correlating with better outcomes in a number of cancer types. Yet a substantial number of cancer patients with high PDCD4 in tumors have poor survival, suggesting that oncogenic pathways may inhibit or change PDCD4 function. Here, we explore the significance of PDCD4 in breast cancer and identify protein arginine methyltransferase 5 (PRMT5) as a cofactor that radically alters PDCD4 function. Specifically, we find that coexpression of PDCD4 and PRMT5 in an orthotopic model of breast cancer causes accelerated tumor growth and that this growth phenotype is dependent on both the catalytic activity of PRMT5 and a site of methylation within the N-terminal region of PDCD4. In agreement with the xenograft model, elevated PDCD4 expression was found to correlate with worse outcome within the cohort of breast cancer patients whose tumors contain higher levels of PRMT5. These results reveal a new cofactor for PDCD4 that alters its tumor suppressor functions and point to the utility of PDCD4/PRMT5 status as both a prognostic biomarker and a potential target for chemotherapy.

Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4.

La mort cellulaire programm&eacute;e 4 (PDCD4) a &eacute;t&eacute; d&eacute;crit comme un suppresseur de tumeur, avec une expression forte corr&eacute;lation avec les meilleurs r&eacute;sultats dans un certain nombre de types de cancer. Encore un nombre important de patients atteints de cancer avec PDCD4 &eacute;lev&eacute; dans les tumeurs ont pi&egrave;tre taux de survie, ce qui sugg&egrave;re que les voies oncog&eacute;niques peuvent inhiber ou modifier la fonction PDCD4. Ici, nous explorons la signification de PDCD4 dans le cancer du sein et identifier la prot&eacute;ine arginine m&eacute;thyltransf&eacute;rase 5 (PRMT5) comme cofacteur qui modifie radicalement la fonction de PDCD4. Plus pr&eacute;cis&eacute;ment, nous trouvons que coexpression de PDCD4 et PRMT5 dans un mod&egrave;le orthotopique du cancer du sein provoque la croissance tumorale acc&eacute;l&eacute;r&eacute;e et que ce ph&eacute;notype de croissance d&eacute;pend de l&#39;activit&eacute; catalytique de PRMT5 et un site de m&eacute;thylation au sein de la r&eacute;gion N-terminale de PDCD4. En accord avec le mod&egrave;le de x&eacute;nogreffe, expression &eacute;lev&eacute;e de PDCD4 a &eacute;t&eacute; trouv&eacute;e en corr&eacute;lation avec le pire r&eacute;sultat au sein de la cohorte de patientes dont les tumeurs contiennent des niveaux plus &eacute;lev&eacute;s de PRMT5. Ces r&eacute;sultats r&eacute;v&egrave;lent un nouvel cofacteur pour PDCD4 qui modifie ses fonctions de suppresseur de tumeur et soulignent l&#39;utilit&eacute; de statut PDCD4/PRMT5 en tant que biomarqueur pronostique et une cible potentielle pour la chimioth&eacute;rapie.

Protein arginine m&eacute;thyltransf&eacute;rase 5 acc&eacute;l&egrave;re la croissance tumorale par m&eacute;thylation de l&#39;arginine de la mort de cellules tumorales suppresseur programm&eacute; 4.

Programmierter Zelltod 4 (PDCD4) wurde als Tumorsuppressor, mit hohen Ausdruck Korrelation mit besseren Ergebnissen in einer Reihe von Krebsarten beschrieben. Noch eine betr&auml;chtliche Anzahl von Krebspatienten mit hohen PDCD4 in Tumoren schlecht &uuml;berleben, darauf hindeutet, dass Onkogene Wege k&ouml;nnen hemmen oder PDCD4-Funktion zu &auml;ndern. Hier erkunden wir die Bedeutung von PDCD4 in Brustkrebs und Protein Arginin Methyltransferase 5 (PRMT5) zu identifizieren, als Kofaktor, der PDCD4-Funktion radikal &auml;ndert. Insbesondere finden wir, dass Coexpression von PDCD4 und PRMT5 Orthotopic Modell von Brustkrebs verursacht beschleunigtes Tumorwachstum und dass dieses Wachstum-Ph&auml;notyp sowohl der katalytischen Wirkung des PRMT5 und ein Standort der Methylierung innerhalb der N-terminalen Region von PDCD4 abh&auml;ngig ist. Im Einvernehmen mit dem Xenograft--Modell wurde erh&ouml;hten PDCD4 Ausdruck gefunden, um mit schlechteren Ergebnis innerhalb der Kohorte von Brustkrebspatientinnen zu korrelieren, deren Tumoren h&ouml;heren PRMT5 enthalten. Diese Ergebnisse zeigen neue Kofaktor f&uuml;r PDCD4, die seine Tumor-Suppressor-Funktionen und der Punkt, um das Dienstprogramm von PDCD4/PRMT5 Status als prognostische Biomarker und ein potenzielles Ziel f&uuml;r Chemotherapie ver&auml;ndert.

Protein Arginin Methyltransferase 5 beschleunigt Tumorwachstum durch Arginin-Methylierung der Tumor Schutzbeschaltung programmierten Zelle Tod 4.

Morte programmata delle cellule 4 (PDCD4) &egrave; stata descritta come un soppressore del tumore, con espressione alta correlazione con i risultati migliori in un certo numero di tipi di cancro. Ancora un notevole numero di pazienti affetti da tumore con alta PDCD4 in tumori hanno scarsa sopravvivenza, suggerendo che percorsi oncogenica possono inibire o modificare la funzione PDCD4. Qui, esploreremo il significato del PDCD4 nel cancro della mammella e identificare proteine arginina methyltransferase 5 (PRMT5) come cofattore che altera radicalmente la funzione PDCD4. In particolare, troviamo che coexpression di PDCD4 e PRMT5 in un modello ortotopico di cancro al seno provoca tumore accelerata crescita e che questo fenotipo di crescita dipende sia l&#39;attivit&agrave; catalitica di PRMT5 e un sito di metilazione all&#39;interno della regione N-terminale di PDCD4. In accordo con il modello xenoinnesto, elevata espressione di PDCD4 &egrave; stato trovato per correlare con esito peggiore all&#39;interno della coorte di pazienti affetti da cancro del seno cui tumori contengono livelli elevati di PRMT5. Questi risultati rivelano un cofattore nuovo per PDCD4 che altera le sue funzioni soppressore tumorale e punto per l&#39;utilit&agrave; di PDCD4/PRMT5 status sia come un biomarcatore prognostico e un potenziale bersaglio per la chemioterapia.

Proteina arginina methyltransferase 5 accelera la crescita tumorale di metilazione di arginina della morte della cellula tumorale soppressore programmato 4.

&#x30D7;&#x30ED;&#x30B0;&#x30E9;&#x30E0;&#x7D30;&#x80DE;&#x6B7B; 4 (PDCD4) &#x306F;&#x816B;&#x760D;&#x306E;&#x30B5;&#x30D7;&#x30EC;&#x30C3;&#x30B5;&#x30FC;&#x3068;&#x3057;&#x3066;&#x3088;&#x308A;&#x826F;&#x3044;&#x6210;&#x679C;&#x306E;&#x304C;&#x3093;&#x306E;&#x7A2E;&#x985E;&#x306E;&#x6570;&#x306B;&#x76F8;&#x95A2;&#x95A2;&#x9023;&#x3065;&#x3051;&#x308B;&#x3053;&#x3068;&#x9AD8;&#x767A;&#x73FE;&#x8A18;&#x8F09;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x307E;&#x3060;&#x76F8;&#x5F53;&#x6570;&#x9AD8; PDCD4 &#x816B;&#x760D;&#x306B;&#x304A;&#x3051;&#x308B;&#x304C;&#x3093;&#x60A3;&#x8005;&#x306E;&#x767A;&#x764C;&#x7D4C;&#x8DEF;&#x3092;&#x963B;&#x5BB3;&#x307E;&#x305F;&#x306F; PDCD4 &#x95A2;&#x6570;&#x3092;&#x5909;&#x66F4;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3001;&#x8CA7;&#x3057;&#x3044;&#x4EBA;&#x3005; &#x306E;&#x751F;&#x5B58;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x6211;&#x3005; &#x306E; PDCD4 &#x306E;&#x610F;&#x7FA9;&#x3092;&#x63A2;&#x308B;&#x4E73;&#x304C;&#x3093;&#x3057;&#x3001;&#x6839;&#x672C;&#x7684;&#x306B; PDCD4 &#x95A2;&#x6570;&#x3092;&#x5909;&#x66F4;&#x56E0;&#x5B50;&#x3068;&#x3057;&#x3066;&#x86CB;&#x767D;&#x8CEA;&#x30A2;&#x30EB;&#x30AE;&#x30CB;&#x30F3; &#x30E1;&#x30C1;&#x30EB;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30D5;&#x30A7;&#x30E9;&#x30FC;&#x30BC; 5 (PRMT5) &#x3092;&#x8B58;&#x5225;&#x3057;&#x307E;&#x3059;&#x3002;&#x5177;&#x4F53;&#x7684;&#x306B;&#x306F;&#x3001;&#x6211;&#x3005; &#x306F;&#x898B;&#x3064;&#x3051;&#x308B;&#x305D;&#x306E; PDCD4 &#x306E;&#x767A;&#x73FE;&#x3068;&#x4E73;&#x764C;&#x306E;&#x52A0;&#x7642;&#x30E2;&#x30C7;&#x30EB;&#x306B;&#x304A;&#x3044;&#x3066; PRMT5 &#x52A0;&#x901F;&#x306E;&#x816B;&#x760D;&#x306E;&#x6210;&#x9577;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3059;&#x3057;&#x3001;&#x3053;&#x306E;&#x6210;&#x9577;&#x306E;&#x8868;&#x73FE;&#x578B;&#x304C; PRMT5 &#x306E;&#x4E21;&#x65B9;&#x89E6;&#x5A92;&#x6D3B;&#x6027;&#x3068; PDCD4 &#x306E; N &#x672B;&#x7AEF;&#x9818;&#x57DF;&#x5185;&#x306E;&#x30E1;&#x30C1;&#x30EB;&#x5316;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x306B;&#x4F9D;&#x5B58;&#x3057;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3002;&#x7570;&#x7A2E;&#x79FB;&#x690D;&#x30E2;&#x30C7;&#x30EB;&#x3068;&#x306E;&#x5408;&#x610F;&#x306F;&#x3001;&#x9AD8;&#x67B6; PDCD4 &#x5F0F; PRMT5 &#x306E;&#x3088;&#x308A;&#x9AD8;&#x3044;&#x30EC;&#x30D9;&#x30EB;&#x3001;&#x816B;&#x760D;&#x3092;&#x542B;&#x3080;&#x4E73;&#x304C;&#x3093;&#x60A3;&#x8005;&#x306E;&#x30B3;&#x30DB;&#x30FC;&#x30C8;&#x5185;&#x60AA;&#x3044;&#x7D50;&#x679C;&#x3068;&#x76F8;&#x95A2;&#x3092;&#x8A8D;&#x3081;&#x305F;.&#x3053;&#x308C;&#x3089;&#x306E;&#x7D50;&#x679C;&#x304B;&#x3089;&#x65B0;&#x3057;&#x3044;&#x88DC;&#x56E0;&#x5B50;&#x305D;&#x306E;&#x816B;&#x760D;&#x30B5;&#x30D7;&#x30EC;&#x30C3;&#x30B5;&#x30FC;&#x6A5F;&#x80FD;&#x304A;&#x3088;&#x3073;&#x30E6;&#x30FC;&#x30C6;&#x30A3;&#x30EA;&#x30C6;&#x30A3;&#x306B;&#x30DD;&#x30A4;&#x30F3;&#x30C8; PDCD4/PRMT5 &#x30B9;&#x30C6;&#x30FC;&#x30BF;&#x30B9;&#x306E;&#x4E88;&#x5F8C;&#x30D0;&#x30A4;&#x30AA; &#x30DE;&#x30FC;&#x30AB;&#x30FC;&#x3068;&#x5316;&#x5B66;&#x7642;&#x6CD5;&#x306E;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3068;&#x3057;&#x3066;&#x5909;&#x3048;&#x308B; PDCD4 &#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x307E;&#x3059;&#x3002;

&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x30A2;&#x30EB;&#x30AE;&#x30CB;&#x30F3; &#x30E1;&#x30C1;&#x30EB;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30D5;&#x30A7;&#x30E9;&#x30FC;&#x30BC; 5 &#x816B;&#x760D;&#x5897;&#x6B96;&#x306B;&#x3088;&#x308B;&#x816B;&#x760D;&#x30B5;&#x30D7;&#x30EC;&#x30C3;&#x30B5;&#x30FC;&#x306E;&#x30D7;&#x30ED;&#x30B0;&#x30E9;&#x30E0;&#x3055;&#x308C;&#x305F;&#x7D30;&#x80DE;&#x6B7B; 4 &#x306E;&#x30A2;&#x30EB;&#x30AE;&#x30CB;&#x30F3;&#x306E;&#x30E1;&#x30C1;&#x30EB;&#x5316;&#x3092;&#x52A0;&#x901F;&#x3057;&#x307E;&#x3059;&#x3002;

&#xD504;&#xB85C;&#xADF8;&#xB7A8; &#xB41C; &#xC138;&#xD3EC; &#xC8FD;&#xC74C; 4 (PDCD4) &#xC885;&#xC591; &#xC5B5;&#xC81C;&#xAE30; &#xB192;&#xC740; &#xC2DD;&#xACFC; &#xB2E4;&#xC591; &#xD55C; &#xC554; &#xC885;&#xB958;&#xC5D0;&#xC5D0;&#xC11C; &#xB354; &#xB098;&#xC740; &#xACB0;&#xACFC; &#xD568;&#xAED8; &#xC124;&#xBA85; &#xD588;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098; &#xC0C1;&#xB2F9;&#xC218; &#xC554; &#xD658;&#xC790; &#xC885;&#xC591;&#xC5D0;&#xC11C; &#xB192;&#xC740; PDCD4 &#xAE08;&#xD558;&#xB294; &#xACBD;&#xB85C; &#xC5B5;&#xC81C; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xB610;&#xB294; PDCD4 &#xD568;&#xC218;&#xB97C; &#xBCC0;&#xACBD; &#xC81C;&#xC548; &#xAC00;&#xB09C;&#xD55C; &#xC0DD;&#xC874;&#xC774; &#xC788;&#xB2E4;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC; pdcd4&#xC5D0;&#xC11C;&#xC758; &#xC758;&#xBBF8; &#xD0D0;&#xAD6C; &#xC720;&#xBC29;&#xC554;&#xACFC; &#xADFC;&#xBCF8;&#xC801;&#xC73C;&#xB85C; PDCD4 &#xD568;&#xC218;&#xB97C; &#xBCC0;&#xACBD; &#xD558;&#xB294; cofactor&#xB85C; &#xB2E8;&#xBC31;&#xC9C8; &#xC544;&#xB974;&#xAE30;&#xB2CC; methyltransferase 5 (PRMT5)&#xB97C; &#xC2DD;&#xBCC4; &#xD569;&#xB2C8;&#xB2E4;. &#xD2B9;&#xD788;, &#xC6B0;&#xB9AC; pdcd4&#xC758; coexpression &#xADF8;&#xB97C; &#xCC3E;&#xC744; &#xC720;&#xBC29;&#xC554;&#xC758; orthotopic &#xBAA8;&#xB378;&#xC5D0;&#xC11C; prmt5&#xB85C; &#xC778;&#xD574; &#xAC00;&#xC18D;&#xD654; &#xB41C; &#xC885;&#xC591;&#xC758; &#xC131;&#xC7A5; &#xBC0F; &#xC131;&#xC7A5; &#xD615;&#xC774; prmt5&#xC758; &#xCD09;&#xB9E4; &#xD65C;&#xB3D9; &#xBAA8;&#xB450; pdcd4&#xC758; N &#xB2E8;&#xC790; &#xC601;&#xC5ED; &#xB0B4;&#xC5D0;&#xC11C; &#xBA54; &#xD2F8; &#xD654; &#xC0AC;&#xC774;&#xD2B8;&#xC5D0; &#xB530;&#xB77C; &#xB2EC;&#xB77C; &#xC9D1;&#xB2C8;&#xB2E4;. &#xB1CC;&#xC885;&#xC591; &#xBAA8;&#xB378; &#xACC4;&#xC57D; &#xB192;&#xC740; PDCD4 &#xC2DD; &#xB204;&#xAD6C;&#xC758; &#xC885;&#xC591; prmt5&#xC758; &#xC0C1;&#xBD80;&#xB97C; &#xD3EC;&#xD568; &#xD558;&#xB294; &#xC720; &#xBC29; &#xC554; &#xD658;&#xC790;&#xC758; &#xCF54; &#xD638;&#xD2B8; &#xB0B4;&#xC5D0;&#xC11C; &#xB354; &#xB098;&#xC05C; &#xACB0;&#xACFC;&#xC640; &#xC0C1;&#xAD00; &#xAD00;&#xACC4;&#xB97C; &#xBC1C;&#xACAC; &#xB410;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; &#xC885;&#xC591; &#xC5B5;&#xC81C; &#xAE30;&#xB2A5; &#xBC0F; &#xC720;&#xD2F8;&#xB9AC;&#xD2F0; PDCD4/PRMT5 &#xC0C1;&#xD0DC; &#xC9C0;&#xC810;&#xC758; &#xC804;&#xC870; biomarker &#xBC0F; &#xD654;&#xD559;&#xC694;&#xBC95;&#xC5D0; &#xB300; &#xD55C; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xB300;&#xC0C1;&#xC73C;&#xB85C; &#xBCC0;&#xACBD; &#xD558;&#xB294; pdcd4&#xC5D0; &#xB300; &#xD55C; &#xC0C8;&#xB85C;&#xC6B4; cofactor &#xACF5;&#xAC1C;.

&#xB2E8;&#xBC31;&#xC9C8; &#xC544;&#xB974;&#xAE30;&#xB2CC; methyltransferase 5 &#xC544;&#xB974;&#xAE30;&#xB2CC; &#xC885;&#xC591; &#xC5B5;&#xC81C; &#xD504;&#xB85C;&#xADF8;&#xB7A8; &#xB41C; &#xC138;&#xD3EC; &#xC8FD;&#xC74C; 4&#xC758; &#xBA54; &#xD2F8; &#xD654;&#xC5D0; &#xC758;&#xD574; &#xC885;&#xC591;&#xC758; &#xC131;&#xC7A5;&#xC744; &#xAC00;&#xC18D; &#xD654;&#xD569;&#xB2C8;&#xB2E4;.

Muerte celular programada 4 (PDCD4) ha sido descrita como un supresor tumoral, con expresi&oacute;n alta correlaci&oacute;n con mejores resultados en varios tipos de c&aacute;ncer. Sin embargo un n&uacute;mero considerable de pacientes de c&aacute;ncer con alta PDCD4 en tumores tiene pobre supervivencia, sugiriendo que v&iacute;as oncog&eacute;nicas pueden inhibir o cambiar la funci&oacute;n de PDCD4. Aqu&iacute;, exploraremos el significado de PDCD4 en c&aacute;ncer de mama e identificar la prote&iacute;na arginina methyltransferase 5 (PRMT5) como un cofactor que altera radicalmente la funci&oacute;n de PDCD4. En concreto, nos encontramos con que el coexpression de PDCD4 y PRMT5 en un modelo ortot&oacute;pico de c&aacute;ncer de mama causa crecimiento acelerado del tumor y que este fenotipo de crecimiento depende tanto de la actividad catal&iacute;tica de PRMT5 y un sitio de metilaci&oacute;n en la regi&oacute;n N-terminal de PDCD4. De acuerdo con el modelo de xenoinjerto, elevada expresi&oacute;n de PDCD4 se encontr&oacute; correlacionar con peor resultado en la cohorte de pacientes con c&aacute;ncer de mama cuyos tumores contienen altos niveles de PRMT5. Estos resultados revelan un cofactor nuevo para PDCD4 que altera sus funciones de supresor del tumor y se&ntilde;alan la utilidad de PDCD4/PRMT5 estado como un biomarcador pron&oacute;stico tanto un objetivo potencial para la quimioterapia.

Prote&iacute;na arginina methyltransferase 5 acelera el crecimiento del tumor por metilaci&oacute;n de arginina de la muerte de c&eacute;lulas de tumor supresor programado 4.

The role of programmed cell death 4 (PDCD4) in tumor biology is context-dependent. PDCD4 is described as a tumor suppressor, but its coexpression with protein arginine methyltransferase 5 (PRMT5) promotes accelerated tumor growth. Here, we report that PDCD4 is methylated during nutrient deprivation. Methylation occurs because of increased stability of PDCD4 protein as well as increased activity of PRMT5 toward PDCD4. During nutrient deprivation, levels of methylated PDCD4 promote cell viability, which is dependent on an enhanced interaction with eIF4A. Upon recovery from nutrient deprivation, levels of methylated PDCD4 are regulated by phosphorylation, which controls both the localization and stability of methylated PDCD4. This study reveals that, in response to particular environmental cues, the role of PDCD4 is up-regulated and is advantageous for cell viability. These findings suggest that the methylated form of PDCD4 promotes tumor viability during nutrient deprivation, ultimately allowing the tumor to grow more aggressively.

Enhanced arginine methylation of programmed cell death 4 protein during nutrient deprivation promotes tumor cell viability.

Resistance to chemotherapy drugs is a serious therapeutic problem and its underlying molecular mechanisms are complex. Stress granules (SGs), cytoplasmic ribonucleoprotein complexes assembled in cells exposed to stress, are implicated in various aspects of cancer cell metabolism and survival. SGs promote the survival of stressed cells by reprogramming gene expression and inhibiting pro-apoptotic signaling cascades. We show that the vinca alkaloid (VA) class of anti-neoplastic agents potently activates a SG-mediated stress response program. VAs inhibit translation initiation by simultaneous activation of eIF4E-BP1 and phosphorylation of eIF2α, causing polysome disassembly and SG assembly. VA-induced SGs contain canonical SG components but lack specific signaling molecules. Blocking VA-induced SG assembly by inactivating eIF4EBP1 or inhibiting eIF2α phosphorylation decreases cancer cell viability and promotes apoptosis. Our data describe previously unappreciated effects of VAs on cellular RNA metabolism and illuminate the roles of SGs in cancer cell survival.

Vinca alkaloid drugs promote stress-induced translational repression and stress granule formation.

Angiogenin (ANG) is a secreted ribonuclease best known for its ability to promote formation of blood vessels. Extensive research over many years has elucidated its structure and biophysical properties, although our knowledge of molecular mechanisms underlying ANG-associated biologic processes remains limited. Intriguingly, many of processes require the ribonuclease activity of ANG, thus highlighting the importance of identifying and characterizing RNA targets and intermediates of ANG-mediated endonucleolytic cleavage. While ANG demonstrates ribonuclease activity toward many RNA substrates in vitro, specific target of ANG, namely mature tRNA, was only recently identified in vivo. ANG-mediated tRNA cleavage is an unorthodox manner of generating non-coding RNAs with diverse biologic activities. In addition, the ribonuclease activity of ANG has been reported to be crucial for rRNA transcription. Here we critically discuss various aspects of ANG biology related to its RNase activity and discuss areas in need of further investigation.

RNA biology of angiogenin: Current state and perspectives.

Cells have developed different mechanisms to respond to stress, including the formation of cytoplasmic foci known as stress granules (SGs). SGs are dynamic and formed as a result of stress-induced inhibition of translation. Despite enormous interest in SGs due to their contribution to the pathogenesis of several human diseases, many aspects of SG formation are poorly understood. SGs induced by different stresses are generally assumed to be uniform, although some studies suggest that different SG subtypes and SG-like cytoplasmic foci exist. Here, we investigated the molecular mechanisms of SG assembly and characterized their composition when induced by various stresses. Our data revealed stress-specific differences in composition, assembly and dynamics of SGs and SG-like cytoplasmic foci. Using a set of genetically modified haploid human cells, we determined the molecular circuitry of stress-specific translation inhibition upstream of SG formation and its relation to cell survival. Finally, our studies characterize cytoplasmic stress-induced foci related to, but distinct from, canonical SGs, and also introduce haploid cells as a valuable resource to study RNA granules and translation control mechanisms.

Marta M. Fay

Division of Rheumatology,
Immunology,
and Allergy,
Division of Rheumatology, Immunology, and Allergy

Brigham and Women's Hospital

Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules

Marta M. Fay

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Brigham and Women's Hospital

Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules

Division of Rheumatology,
Immunology,
and Allergy,
Division of Rheumatology, Immunology, and Allergy