utilizing-murine-inducible-telomerase-alleles-studies-tissue

Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer

Telomere dysfunction-induced loss of genome integrity and its associated DNA damage signaling and checkpoint responses are well-established drivers that ...

Sanofi US

&#x524D;&#x5217;&#x817A;&#x764C;&#x662F;&#x7537;&#x6027;&#x764C;&#x75C7;&#x76F8;&#x5173;&#x6B7B;&#x4EA1;&#x7684;&#x7B2C;&#x4E8C;&#x4E2A;&#x4E3B;&#x8981;&#x539F;&#x56E0;&#x3002;MAP &#x6FC0;&#x9176;&#x4FE1;&#x53F7;&#x901A;&#x8DEF;&#x7684;&#x6FC0;&#x6D3B;&#x6709;&#x7275;&#x8FDE;&#x5728;&#x5148;&#x8FDB;&#x548C;&#x96C4;&#x6FC0;&#x7D20;&#x4F9D;&#x8D56;&#x6027;&#x524D;&#x5217;&#x817A;&#x764C;&#xFF0C;&#x867D;&#x7136;&#x4E00;&#x76F4;&#x7F3A;&#x4E4F;&#x6B63;&#x5F0F;&#x7684;&#x9057;&#x4F20;&#x8BC1;&#x636E;&#x3002;&#x5728;&#x8FC7;&#x7A0B;&#x4E2D;&#x7684;&#x916A;&#x6C28;&#x9178;&#x9176;&#x542F;&#x52A8;&#x5B50;&#x7684;&#x8F6C;&#x57FA;&#x56E0;&#x7CFB;&#x7EDF;&#x5EFA;&#x6A21;&#x6076;&#x6027;&#x9ED1;&#x8272;&#x7D20;&#x7624;&#x3001; &#x6211;&#x4EEC;&#x5F00;&#x53D1;&#x57FA;&#x56E0;&#x5DE5;&#x7A0B;&#x5C0F;&#x9F20; &#xFF08;GEM&#xFF09; &#x6A21;&#x578B;&#x7684;&#x4FB5;&#x88AD;&#x6027;&#x524D;&#x5217;&#x817A;&#x764C;&#xFF0C;&#x5373;&#x4E00;&#x79CD;&#x6D3B;&#x5316;&#x7A81;&#x53D8;&#x7684; BRAF (V600E) &mdash; &mdash; &#x5927;&#x7EA6; 10%&#x7684;&#x4EBA;&#x7C7B;&#x524D;&#x5217;&#x817A;&#x764C;&#x7EC4;&#x7EC7;&#x4E2D;&#x53D1;&#x73B0;&#x7684;&#x7A81;&#x53D8; &mdash; &mdash; &#x9488;&#x5BF9;&#x80CC;&#x666F;&#x4E0B; Ink4a/&#x6025;&#x6027;&#x80BE;&#x529F;&#x80FD;&#x8870;&#x7AED;&#x75C7;&#x7684;&#x524D;&#x5217;&#x817A;&#x4E0A;&#x76AE;&#x8F66;&#x53A2;&#x5185;&#x3002;&#x8FD9;&#x4E9B;&#x5B9D;&#x77F3;&#x5C0F;&#x9F20;&#x5F00;&#x53D1;&#x8FDB;&#x5C55;&#x81F3;&#x6CA1;&#x6709; AKT &#x6FC0;&#x6D3B;&#xFF0C;&#x63D0;&#x4F9B;&#x7684;&#x5730;&#x56FE;&#x6FC0;&#x9176;&#x4FE1;&#x53F7;&#x6FC0;&#x6D3B;&#x662F;&#x8DB3;&#x4EE5;&#x9A71;&#x52A8;&#x524D;&#x5217;&#x817A;&#x80BF;&#x7624;&#x53D1;&#x751F;&#x7684;&#x9057;&#x4F20;&#x8BC1;&#x636E;&#x7684;&#x8BC1;&#x636E;&#x8FC5;&#x901F;&#x589E;&#x957F;&#x521B;&#x817A;&#x764C;&#x524D;&#x5217;&#x817A;&#x589E;&#x751F;&#x75C7;&#x3002;&#x91CD;&#x8981;&#x7684;&#x662F;&#xFF0C;BRAF(V600E) &#x5728;&#x65E2;&#x5B9A;&#x7684;&#x524D;&#x5217;&#x817A;&#x80BF;&#x7624;&#x7684;&#x9057;&#x4F20;&#x706D;&#x7EDD;&#x5E76;&#x6CA1;&#x6709;&#x5BFC;&#x81F4;&#x80BF;&#x7624;&#x56DE;&#x5F52;&#xFF0C;&#x6307;&#x793A;&#x867D;&#x7136;&#x4E0D;&#x8DB3;&#x4EE5;&#x542F;&#x52A8;&#x4FB5;&#x88AD;&#x6027;&#x524D;&#x5217;&#x817A;&#x764C;&#x7684;&#x53D1;&#x5C55;&#xFF0C;BRAF(V600E) &#x4E0D;&#x9700;&#x8981;&#x7EF4;&#x4FEE;&#x3002;

BRAF &#x6FC0;&#x6D3B;&#x5C06;&#x542F;&#x52A8;&#xFF0C;&#x4F46;&#x4E0D;&#x7EF4;&#x62A4;&#x4FB5;&#x88AD;&#x6027;&#x524D;&#x5217;&#x817A;&#x764C;&#x3002;

Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAF(V600E)--a mutation found in approximately 10% of human prostate tumors--was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAF(V600E) in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAF(V600E) is not required for its maintenance.

BRAF activation initiates but does not maintain invasive prostate adenocarcinoma.

Cancer de la prostate est la deuxi&#xE8;me cause de d&#xE9;c&#xE8;s li&#xE9;s au cancer chez les hommes. L&#x26;#39;activation de la kinase MAP voie de signalisation a &#xE9;t&#xE9; impliqu&#xE9; dans les cancers de la prostate avanc&#xE9; et androg&#xE9;no-ind&#xE9;pendant, bien que la preuve g&#xE9;n&#xE9;tique formelle a fait d&#xE9;faut. Dans le cadre de la mod&#xE9;lisation de m&#xE9;lanome malin dans un syst&#xE8;me de promoteur tyrosinase transg&#xE9;nique, nous avons d&#xE9;velopp&#xE9; une souris g&#xE9;n&#xE9;tiquement modifi&#xE9;e (GEM) de cancers de la prostate envahissantes, dans lequel une mutation activatrice du g&#xE8;ne BRAF (V600E) - une mutation trouv&#xE9;e dans environ 10% des ressources humaines tumeurs de la prostate - a &#xE9;t&#xE9; la cible dans le compartiment &#xE9;pith&#xE9;lial de la glande de la prostate sur le fond de la carence en INK4a/ARF. Ces souris GEM d&#xE9;velopp&#xE9; une hyperplasie de la prostate avec une progression &#xE0; croissance rapide ad&#xE9;nocarcinome invasif sans preuve d&#x26;#39;activation AKT, apportant la preuve g&#xE9;n&#xE9;tique que l&#x26;#39;activation de la MAP kinase de signalisation est suffisante pour entra&#xEE;ner la tumorigen&#xE8;se de la prostate. Surtout, l&#x26;#39;extinction g&#xE9;n&#xE9;tique du g&#xE8;ne BRAF (V600E) dans les tumeurs de la prostate &#xE9;tablies n&#x26;#39;ont pas conduit &#xE0; une r&#xE9;gression tumorale, indiquant que, bien que suffisante pour amorcer le d&#xE9;veloppement de l&#x26;#39;ad&#xE9;nocarcinome de la prostate invasif, BRAF (V600E) n&#x26;#39;est pas n&#xE9;cessaire pour son entretien.

Activation BRAF Initi&#xE9;s, mais ne maintient pas ad&#xE9;nocarcinome de la prostate envahissantes

Prostatakrebs ist die zweite f&uuml;hrende Ursache der Krebs-in Verbindung stehenden Todesf&auml;lle bei M&auml;nnern. Aktivierung der MAP-Kinase signalisieren Weg hat in Erweiterte und Androgen-unabh&auml;ngigen Prostatakrebs spielen, verwickelt, obwohl formaler genetischer Beweis gefehlt hat. Im Zuge der Modellierung malignen Melanoms in einem Tyrosinase Projekttr&auml;ger transgene System, entwickelten wir eine gentechnisch (GEM) Mausmodell der invasiven Krebsf&auml;lle, wobei eine aktivierende Mutation des BRAF (V600E)--eine Mutation gefunden bei etwa 10 % der menschlichen Prostatatumoren--zum epitheliale Fach der Prostata auf dem Hintergrund des Ink4a/Arf-Mangels ausgerichtet war. Diese GEM-M&auml;use entwickelt Prostatahyperplasie mit Fortschreiten zu schnell wachsenden invasiven Adenokarzinom ohne Anhaltspunkte AKT-Aktivierung genetischer Beweis erbringen, dass Aktivierung MAP Kinase signalisieren Prostata Tumorigenese fahren ausreicht. Wichtig ist, f&uuml;hrten genetische Aussterben BRAF(V600E) etablierten Prostatatumoren nicht zur Tumorr&uuml;ckbildung f&uuml;hrt, darauf hinweist, dass zwar ausreichend, um die Entwicklung der invasiven Prostata Adenokarzinom initiieren, BRAF(V600E) nicht f&uuml;r seine Wartung ben&ouml;tigt.

BRAF-Aktivierung initiiert, aber beh&auml;lt nicht invasiven Prostata Adenokarzinom.

Il cancro della prostata &egrave; la seconda principale causa di decessi per cancro negli uomini. Attivazione della chinasi mappa signaling pathway &egrave; stato implicato nei tumori della prostata androgeno-indipendente e avanzati, anche se privo di prova genetica formale. Nel corso di modellazione melanoma maligno in un sistema transgenici promotore di tirosinasi, abbiamo sviluppato un modello del mouse geneticamente (GEM) dei tumori della prostata invasivi, per cui una mutazione attiva di BRAF (V600E) - una mutazione trovati in circa il 10% dei tumori della prostata umani - &egrave; stata mirata al compartimento epiteliale della prostata sullo sfondo del deficit Ink4a/Arf. Questi topi GEM sviluppato iperplasia della prostata con progressione a rapida crescita adenocarcinoma invasivo senza evidenza di attivazione di AKT, fornendo la prova genetica che attivazione della chinasi di mappa segnalazione &egrave; sufficiente per guidare la tumorigenesi prostatica. Importante, estinzione genetica di BRAF(V600E) in tumori della prostata stabiliti non ha portato alla regressione del tumore, che indica che mentre sufficienti per avviare lo sviluppo di adenocarcinoma invasivo della prostata, BRAF(V600E) non &egrave; richiesto per la sua manutenzione.

Attivazione di BRAF avvia ma mantenere non invasiva adenocarcinoma della prostata.

&#x524D;&#x7ACB;&#x817A;&#x304C;&#x3093;&#x306F;&#x7537;&#x6027;&#x306E;&#x764C;&#x306B;&#x95A2;&#x9023;&#x3057;&#x305F;&#x6B7B;&#x4EA1;&#x539F;&#x56E0;&#x306E;&#x7B2C;2&#x4F4D;&#x3067;&#x3059;&#x3002;&#x6B63;&#x5F0F;&#x306A;&#x907A;&#x4F1D;&#x7684;&#x8A3C;&#x62E0;&#x304C;&#x6B20;&#x3051;&#x3066;&#x3044;&#x305F;&#x3082;&#x306E;&#x306E;&#x3001;MAP&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x3001;&#x5148;&#x9032;&#x7684;&#x304B;&#x3064;&#x30A2;&#x30F3;&#x30C9;&#x30ED;&#x30B2;&#x30F3;&#x975E;&#x4F9D;&#x5B58;&#x6027;&#x524D;&#x7ACB;&#x817A;&#x764C;&#x306B;&#x95A2;&#x4E0E;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x30C1;&#x30ED;&#x30B7;&#x30CA;&#x30FC;&#x30BC;&#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30B8;&#x30A7;&#x30CB;&#x30C3;&#x30AF;&#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x3067;&#x306F;&#x60AA;&#x6027;&#x9ED2;&#x8272;&#x816B;&#x3092;&#x30E2;&#x30C7;&#x30EB;&#x5316;&#x3059;&#x308B;&#x904E;&#x7A0B;&#x3067;&#x3001;&#x6211;&#x3005;&#x306F;&#x305D;&#x308C;&#x306B;&#x3088;&#x3063;&#x3066;BRAF&#x306E;&#x6D3B;&#x6027;&#x5316;&#x5909;&#x7570;&#xFF08;V600E&#xFF09;&#x3001;&#x4FB5;&#x8972;&#x6027;&#x524D;&#x7ACB;&#x817A;&#x764C;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x6539;&#x5909;&#x30DE;&#x30A6;&#x30B9;&#xFF08;GEM&#xFF09;&#x30E2;&#x30C7;&#x30EB;&#x3092;&#x958B;&#x767A; - &#x4EBA;&#x9593;&#x306E;&#x7D04;10&#xFF05;&#x3067;&#x898B;&#x3064;&#x304B;&#x3063;&#x305F;&#x7A81;&#x7136;&#x5909;&#x7570;&#x524D;&#x7ACB;&#x817A;&#x816B;&#x760D;&#x306F; -  Ink4a/Arf&#x6B20;&#x4E4F;&#x306E;&#x80CC;&#x666F;&#x306B;&#x306F;&#x3001;&#x524D;&#x7ACB;&#x817A;&#x306E;&#x4E0A;&#x76AE;&#x30B3;&#x30F3;&#x30D1;&#x30FC;&#x30C8;&#x30E1;&#x30F3;&#x30C8;&#x306B;&#x6A19;&#x7684;&#x306B;&#x3055;&#x308C;&#x305F;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;GEM&#x30DE;&#x30A6;&#x30B9;&#x306F;&#x3001;&#x6025;&#x901F;&#x306B;MAP&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x524D;&#x7ACB;&#x817A;&#x816B;&#x760D;&#x3092;&#x99C6;&#x52D5;&#x3059;&#x308B;&#x306E;&#x306B;&#x5341;&#x5206;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x907A;&#x4F1D;&#x7684;&#x8A3C;&#x62E0;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x3001;AKT&#x6D3B;&#x6027;&#x5316;&#x306E;&#x8A3C;&#x62E0;&#x3082;&#x306A;&#x3057;&#x306B;&#x6D78;&#x6F64;&#x817A;&#x764C;&#x306E;&#x6210;&#x9577;&#x306B;&#x9032;&#x884C;&#x3057;&#x3066;&#x524D;&#x7ACB;&#x817A;&#x904E;&#x5F62;&#x6210;&#x3092;&#x958B;&#x767A;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x91CD;&#x8981;&#x306A;&#x306E;&#x306F;&#x3001;&#x78BA;&#x7ACB;&#x3055;&#x308C;&#x305F;&#x524D;&#x7ACB;&#x817A;&#x816B;&#x760D;&#x306B;&#x304A;&#x3051;&#x308B;BRAF&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x7D76;&#x6EC5;&#xFF08;V600E&#xFF09;&#x306F;&#x3001;&#x4FB5;&#x8972;&#x6027;&#x524D;&#x7ACB;&#x817A;&#x764C;&#x306E;&#x958B;&#x767A;&#x3092;&#x958B;&#x59CB;&#x3059;&#x308B;&#x306E;&#x306B;&#x5341;&#x5206;&#x306A;&#x4E00;&#x65B9;&#x3067;&#x3001;BRAF&#xFF08;V600E&#xFF09;&#x304C;&#x305D;&#x306E;&#x7DAD;&#x6301;&#x306B;&#x5FC5;&#x8981;&#x3068;&#x3055;&#x308C;&#x3066;&#x3044;&#x306A;&#x3044;&#x3053;&#x3068;&#x3092;&#x793A;&#x3059;&#x3001;&#x816B;&#x760D;&#x9000;&#x7E2E;&#x306B;&#x306F;&#x81F3;&#x3089;&#x306A;&#x304B;&#x3063;&#x305F;&#x3002;

BRAF&#x306E;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D9;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306F;&#x958B;&#x59CB;&#x3057;&#x307E;&#x3059;&#x304C;&#x3001;&#x4FB5;&#x8972;&#x6027;&#x524D;&#x7ACB;&#x817A;&#x764C;&#x3092;&#x7DAD;&#x6301;&#x3057;&#x307E;&#x305B;&#x3093;

&#xC804;&#xB9BD;&#xC120; &#xC554;&#xC740; &#xB0A8;&#xC131;&#xC5D0;&#xC11C; &#xC554; &#xAD00;&#xB828; &#xC0AC;&#xB9DD;&#xC758; &#xB450; &#xBC88;&#xC9F8; &#xC8FC;&#xC694; &#xC6D0;&#xC778;. &#xBE44;&#xB85D; &#xACF5;&#xC2DD;&#xC801;&#xC778; &#xC720;&#xC804;&#xC790; &#xC99D;&#xAC70; &#xBD80;&#xC871; &#xD588;&#xB358; &#xC9C0;&#xB3C4; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; &#xC2E0;&#xD638; &#xD1B5;&#xB85C;&#xC758; &#xD65C;&#xC131;&#xD654; &#xACE0;&#xAE09;&#xC774; &#xACE0; &#xC548; &#xB4DC;&#xB85C; &#xAC90; &#xB3C5;&#xB9BD;&#xC801;&#xC778; &#xC804;&#xB9BD;&#xC120; &#xC554;&#xC5D0; &#xC5F0;&#xB8E8; &#xB418;&#xC5B4;&#xC788;&#xB2E4;. Tyrosinase &#xBC1C;&#xAE30;&#xC778; &#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; &#xC2DC;&#xC2A4;&#xD15C;&#xC5D0; &#xC545;&#xC131; &#xD751;&#xC0C9; &#xC885;&#xC744; &#xBAA8;&#xB378;&#xB9C1; &#xD558;&#xB294; &#xACFC;&#xC815;&#xC5D0;&#xC11C; &#xC6B0;&#xB9AC;&#xB294; &#xBE7C;&#xC557;&#xC544; BRAF (V600E)&#xC758; &#xD65C;&#xC131;&#xD654; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;-&#xC778;&#xAC04;&#xC758; &#xC804;&#xB9BD;&#xC120; &#xC885;&#xC591;&#xC758; &#xC57D; 10%&#xC5D0;&#xC11C; &#xBC1C;&#xACAC; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;-Ink4a/Arf &#xACB0;&#xD54D;&#xC758; &#xBC30;&#xACBD;&#xC5D0; &#xC804;&#xB9BD;&#xC120;&#xC758; &#xC0C1;&#xD53C; &#xAD6C;&#xD68D;&#xC744; &#xB300;&#xC0C1;&#xC73C;&#xB85C; &#xCE68; &#xC724; &#xC131; &#xC804;&#xB9BD;&#xC120; &#xC554;&#xC758; &#xC720;&#xC804;&#xC73C;&#xB85C; &#xC124;&#xACC4; &#xB41C; &#xB9C8;&#xC6B0;&#xC2A4; (GEM) &#xBAA8;&#xB378;&#xC744; &#xAC1C;&#xBC1C; &#xD588;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xBCF4;&#xC11D; &#xC0DD;&#xC950; &#xAC1C;&#xBC1C; &#xC9C0;&#xB3C4; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; &#xC2DC;&#xADF8;&#xB110;&#xB9C1;&#xC758; &#xD65C;&#xC131;&#xD654;&#xB294; &#xC804;&#xB9BD;&#xC120; tumorigenesis &#xB4DC;&#xB77C;&#xC774;&#xBE0C;&#xC5D0; &#xCDA9;&#xBD84; &#xD55C; &#xC720;&#xC804;&#xC790; &#xC99D;&#xAC70;&#xB97C; &#xC81C;&#xACF5; &#xD558;&#xB294; AKT &#xD65C;&#xC131;&#xD654;&#xC758; &#xC99D;&#xAC70; &#xC5C6;&#xC774; &#xAE09;&#xC131;&#xC7A5; &#xCE68;&#xB7B5; &#xC120; &#xC554;&#xC73C;&#xB85C; &#xC9C4;&#xD589; &#xB41C; &#xC804;&#xB9BD;&#xC120; &#xBE44; &#xB300; &#xC99D;. &#xC911;&#xC694; &#xD55C; &#xAC83;&#xC740;, BRAF(V600E)&#xC758; &#xC720;&#xC804; &#xBA78;&#xC885; &#xC124;&#xB9BD;&#xB41C; &#xC804;&#xB9BD;&#xC120; &#xC885;&#xC591;&#xC5D0;&#xB294; &#xCE68;&#xB7B5; &#xC801; &#xC804;&#xB9BD;&#xC120; &#xC120; &#xC554; &#xAC1C;&#xBC1C;&#xC744; &#xC2DC;&#xC791; &#xD558;&#xB294; &#xB370; &#xCDA9;&#xBD84;, &#xD558;&#xB294; &#xB3D9;&#xC548; BRAF(V600E) &#xD544;&#xC694; &#xD558;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4; &#xADF8;&#xAC83;&#xC758; &#xC720;&#xC9C0; &#xBCF4;&#xC218;&#xB97C; &#xC704;&#xD574; &#xB098;&#xD0C0;&#xB0B4;&#xB294; &#xC885;&#xC591; &#xD68C;&#xADC0; &#xC774;&#xC5B4;&#xC9C8; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xB2E4;.

BRAF &#xD65C;&#xC131;&#xD654; &#xC2DC;&#xC791; &#xD558;&#xC9C0;&#xB9CC; &#xCE68;&#xB7B5; &#xC801; &#xC804;&#xB9BD;&#xC120; &#xC120; &#xC554;&#xC744; &#xC720;&#xC9C0; &#xD558;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;.

El c&#xE1;ncer de pr&#xF3;stata es la segunda causa principal de muertes relacionadas con c&#xE1;ncer en los hombres. La activaci&#xF3;n de la MAP quinasa v&#xED;a de se&#xF1;alizaci&#xF3;n ha sido implicada en los c&#xE1;nceres de pr&#xF3;stata avanzados y andr&#xF3;geno-independiente, aunque la prueba gen&#xE9;tica formal ha estado ausente. En el curso de modelado de melanoma maligno en un sistema promotor de la tirosinasa transg&#xE9;nico, hemos desarrollado un rat&#xF3;n dise&#xF1;ado gen&#xE9;ticamente (GEM), modelo de los c&#xE1;nceres de pr&#xF3;stata invasivo, por el cual una mutaci&#xF3;n activadora de BRAF (V600E) - una mutaci&#xF3;n se encuentra en aproximadamente el 10% de los derechos humanos los tumores de pr&#xF3;stata - se dirigi&#xF3; al compartimiento epitelial de la gl&#xE1;ndula de la pr&#xF3;stata en el fondo de la deficiencia de INK4a/ARF. Estos ratones desarrollaron GEM hiperplasia de la gl&#xE1;ndula prost&#xE1;tica con la progresi&#xF3;n de r&#xE1;pido crecimiento de adenocarcinoma invasivo, sin evidencia de activaci&#xF3;n de Akt, para aportar la prueba gen&#xE9;tica que la activaci&#xF3;n de MAP quinasa de se&#xF1;alizaci&#xF3;n es suficiente para conducir la tumorig&#xE9;nesis de pr&#xF3;stata. Es importante destacar que la extinci&#xF3;n gen&#xE9;tica de BRAF (V600E) en los tumores de pr&#xF3;stata establecidos no dio lugar a la regresi&#xF3;n del tumor, lo que indica que si bien es suficiente para iniciar el desarrollo de adenocarcinoma de pr&#xF3;stata invasivo, BRAF (V600E) no es necesario para su mantenimiento.

La activaci&#xF3;n de BRAF Inicia pero no mantiene el adenocarcinoma de pr&#xF3;stata invasivo

The PI3K-AKT-FoxO pathway is integral to lifespan regulation in lower organisms and essential for the stability of long-lived cells in mammals. Here, we report the impact of combined FoxO1, 3, and 4 deficiencies on mammalian brain physiology with a particular emphasis on the study of the neural stem/progenitor cell (NSC) pool. We show that the FoxO family plays a prominent role in NSC proliferation and renewal. FoxO-deficient mice show initial increased brain size and proliferation of neural progenitor cells during early postnatal life, followed by precocious significant decline in the NSC pool and accompanying neurogenesis in adult brains. Mechanistically, integrated transcriptomic, promoter, and functional analyses of FoxO-deficient NSC cultures identified direct gene targets with known links to the regulation of human brain size and the control of cellular proliferation, differentiation, and oxidative defense. Thus, the FoxO family coordinately regulates diverse genes and pathways to govern key aspects of NSC homeostasis in the mammalian brain.

FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis.

Telomerase, a ribonucleoprotein complex of hTERT, hTR, and TP1, has been reported to be associated with carcinogenesis and multidrug resistance (MDR). This study used our in vitro human cervical multistep carcinogenesis/MDR model system in which normal human ectocervical and endocervical (HEN) cells were immortalized by HPV18 or 16, respectively, and subsequently transformed. The first evidence was found that immortalization and telomerase activation were correlated with increased expression specifically of two of the hTERT alternatively spliced mRNAs, one encoding wild-type protein containing the full-length functional reverse transcriptase (RT) region and one encoding a defective RT protein. Expression of neither hTERT mRNA containing full-length functional or defective RT motif was affected by transformation/MDR. All-trans-retinoic acid (ATRA) treatment of HPV-immortalized HEN-16-2 cells and transformed/MDR HEN-16-2/CDDP cells inhibited telomerase activity and downregulated expression of hTERT mRNAs containing full-length functional and a defective RT motif, but there were no changes in hTR and TP1 expression. Moreover, ATRA inhibited cell growth rate of HEN-16-2 and HEN-16-2/CDDP cells equally. These results provided the first evidence that ATRA equally in both immortalized and transformed/MDR cell lines inhibits telomerase activity and downregulates expression, but not splicing, of hTERT, and this is correlated with cell growth rate inhibition; the potential is implicated for applying ATRA to hTERT-targeted treatment of cervical cell carcinogenesis/MDR.

Retinoic acid inhibits telomerase activity and downregulates expression but does not affect splicing of hTERT: correlation with cell growth rate inhibition in an in vitro cervical carcinogenesis/multidrug-resistance model.

Sanguinarine, a benzophenanthrine alkaloid, is potentially antineoplastic through induction of cell death pathways. The development of multidrug resistance (MDR) is a major obstacle to the success of chemotherapeutic agents. The aim of this study was to investigate whether sanguinarine is effective against uterine cervical MDR and, if so, by which mechanism. The effects of treatment with sanguinarine on human papillomavirus (HPV) type 16-immortalized endocervical cells and their MDR counterpart cells were compared. Trypan blue exclusion assays and clonogenic survival assays demonstrated that MDR human cervical cells are as sensitive as their drug-sensitive parental cells to death induced by sanguinarine. Upon treatment of both types of cells with sanguinarine, two distinct concentration-dependent modes of cell death were observed. Treatment with 2.12 or 4.24 microM sanguinarine induced death in most cells that was characterized as apoptosis using the criteria of cell surface blebbing, as determined by light and scanning electron microscopy, and proteolytic activation of caspase-3 and cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP), as detected by Western blot analysis. However, 8.48 and 16.96 microM sanguinarine caused a second mode of cell death, oncosis, distinguished by cell surface blistering, and neither caspase-3 activation nor PARP cleavage. This study provides the first evidence that sanguinarine is effective against MDR in cervical cells via bimodal cell death, which displays alternative mechanisms involving different morphologies and caspase-3 activation status.

The alkaloid sanguinarine is effective against multidrug resistance in human cervical cells via bimodal cell death.

mi-er1 (previously called er1) is a fibroblast growth factor-inducible early response gene activated during mesoderm induction in Xenopus embryos and encoding a nuclear protein that functions as a transcriptional activator. The human orthologue of mi-er1 was shown to be upregulated in breast carcinoma cell lines and breast tumours when compared to normal breast cells. In this report, we investigate the structure of the human mi-er1 (hmi-er1) gene and characterize the alternatively spliced transcripts and protein isoforms. hmi-er1 is a single copy gene located at 1p31.2 and spanning 63 kb. It contains 17 exons and includes one skipped exon, a facultative intron and three polyadenylation signals to produce 12 transcripts encoding six distinct proteins. hmi-er1 transcripts were expressed at very low levels in most human adult tissues and the mRNA isoform pattern varied with the tissue. The 12 transcripts encode proteins containing a common internal sequence with variable N- and C-termini. Three distinct N- and two distinct C-termini were identified, giving rise to six protein isoforms. The two C-termini differ significantly in size and sequence and arise from alternate use of a facultative intron to produce hMI-ER1alpha and hMI-ER1beta. In all tissues except testis, transcripts encoding the beta isoform were predominant. hMI-ER1alpha lacks the predicted nuclear localization signal and transfection assays revealed that, unlike hMI-ER1beta, it is not a nuclear protein, but remains in the cytoplasm. Our results demonstrate that alternate use of a facultative intron regulates the subcellular localization of hMI-ER1 proteins and this may have important implications for hMI-ER1 function.

Genomic organization of the human mi-er1 gene and characterization of alternatively spliced isoforms: regulated use of a facultative intron determines subcellular localization.

mi-er1 (previously called er1) was first isolated from Xenopus laevis embryonic cells as a novel fibroblast growth factor-regulated immediate-early gene. Xmi-er1 was shown to encode a nuclear protein with an N-terminal acidic transcription activation domain. The human orthologue of mi-er1 (hmi-er1) displays 91% similarity to the Xenopus sequence at the amino acid level and was shown to be upregulated in breast carcinoma cell lines and tumors. Alternative splicing at the 3' end of hmi-er1 produces two major isoforms, hMI-ER1alpha and hMI-ER1beta, which contain distinct C-terminal domains. In this study, we investigated the role of hMI-ER1alpha and hMI-ER1beta in the regulation of transcription. Using fusion proteins of hMI-ER1alpha or hMI-ER1beta tethered to the GAL4 DNA binding domain, we show that both isoforms, when recruited to the G5tkCAT minimal promoter, function to repress transcription. We demonstrate that this repressor activity is due to interaction and recruitment of a trichostatin A-sensitive histone deacetylase 1 (HDAC1). Furthermore, deletion analysis revealed that recruitment of HDAC1 to hMI-ER1alpha and hMI-ER1beta occurs through their common ELM2 domain. The ELM2 domain was first described in the Caenorhabditis elegans Egl-27 protein and is present in a number of SANT domain-containing transcription factors. This is the first report of a function for the ELM2 domain, highlighting its role in the regulation of transcription.

Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment of histone deacetylase 1 to their conserved ELM2 domain.

To gain insight into the regulation of hmi-er1 expression, we cloned a human genomic DNA fragment containing one of the two hmi-er1 promoters and consisting of 1460 bp upstream of the translation initiation codon of hMI-ER1. Computer-assisted sequence analysis revealed that the hmi-er1 promoter region contains a CpG island but lacks an identifiable TATA element, initiator sequence and downstream promoter element. This genomic DNA was able to direct transcription of a luciferase reporter gene in a variety of human cell lines, and the minimal promoter was shown to be located within-68/+144 bp. Several putative Sp1 binding sites were identified, and we show that Sp1 can bind to the hmi-er1 minimal promoter and increase transcription, suggesting that the level of hmi-er1 expression may depend on the availability of Sp1 protein. Functional analysis revealed that hMI-ER1 represses Sp1-activated transcription from the minimal promoter by a histone deacetylase-independent mechanism. Chromatin immunoprecipitation analysis demonstrated that both Sp1 and hMI-ER1 are associated with the chromatin of the hmi-er1 promoter and that overexpression of hMI-ER1 in cell lines that allow Tet-On-inducible expression resulted in loss of detectable Sp1 from the endogenous hmi-er1 promoter. The mechanism by which this occurs does not involve binding of hMI-ER1 to cis-acting elements. Instead, we show that hMI-ER1 physically associates with Sp1 and that endogenous complexes containing the two proteins could be detected in vivo. Furthermore, hMI-ER1 specifically interferes with binding of Sp1 to the hmi-er1 minimal promoter as well as to an Sp1 consensus oligonucleotide. Deletion analysis revealed that this interaction occurs through a region containing the SANT domain of hMI-ER1. Together, these data reveal a functional role for the SANT domain in the action of co-repressor regulatory factors and suggest that the association of hMI-ER1 with Sp1 represents a novel mechanism for the negative regulation of Sp1 target promoters.

The SANT domain of human MI-ER1 interacts with Sp1 to interfere with GC box recognition and repress transcription from its own promoter.

Aktivierte Phosphoinositid-3-Kinase (PI3K)-AKT Signalisierung scheint ein obligat Ereignis in der Entwicklung von Krebs zu sein. Die stark verbundenen Mitglieder der S&auml;ugetier-FoxO Transkription Erfolgsfaktor Familie, FoxO1, FoxO3 und FoxO4, stellen eine der mehreren Effektor Wappen PI3K-AKT-Signalisierung, woraufhin genetische Analyse der Rolle der FoxOs in der neoplastischen Ph&auml;notypen PI3K-AKT-Aktivierung verkn&uuml;pft. W&auml;hrend Germline oder somatische L&ouml;schung von bis zu f&uuml;nf FoxO Allele bemerkenswert bescheidene neoplastische Ph&auml;notypen produziert, geweckten breiten somatische L&ouml;schung aller FoxOs progressive Krebs neigende Bedingung gekennzeichnet durch Thymom Lymphomen und H&auml;mangiome, verdeutlichen, dass die S&auml;ugetier-FoxOs tats&auml;chlich gutgl&auml;ubiger Tumor Unterdr&uuml;cker sind. Transkriptom und F&ouml;rderer Analysen differentiell betroffenen Endothel entdeckten direkte FoxO und zeigte, dass FoxO Verordnung dieser Ziele in-vivo hoch kontextspezifische, sogar in der gleichen Zelle Art. Funktionsstudien &uuml;berpr&uuml;ft Sprouty2 und PBX1, unter anderem als Vermittler von Endothelzellen Morphogenese und vaskul&auml;re Hom&ouml;ostase FoxO geregelt.

FoxOs sind Linie kalorienarme redundante Tumor Suppressors und Endothelzellen Hom&ouml;ostase zu regulieren.

&#x6FC0;&#x6D3B;&#x78F7;&#x8102;&#x9170;&#x808C;&#x9187; 3-&#x6FC0;&#x9176; (&#x808C;&#x9187;&#xFF09;-AKT &#x4FE1;&#x53F7;&#x4F3C;&#x4E4E;&#x662F;&#x9884;&#x7559;&#x7684;&#x4E8B;&#x4EF6;&#xFF0C;&#x5728;&#x764C;&#x75C7;&#x7684;&#x53D1;&#x5C55;&#x3002;&#x54FA;&#x4E73;&#x52A8;&#x7269; FoxO &#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x5BB6;&#x65CF;&#x3001; FoxO1&#x3001; FoxO3 &#x548C; FoxO4&#xFF0C;&#x9AD8;&#x5EA6;&#x76F8;&#x5173;&#x7684;&#x6210;&#x5458;&#x4EE3;&#x8868;&#x7684;&#x808C;&#x9187; AKT &#x4FE1;&#x53F7;&#xFF0C;&#x63D0;&#x793A; FoxOs &#x7684;&#x4F5C;&#x7528;&#x5728;&#x6076;&#x6027;&#x8868;&#x578B;&#x7684;&#x9057;&#x4F20;&#x5206;&#x6790;&#x6302;&#x94A9;&#x808C;&#x9187; AKT &#x6D3B;&#x5316;&#x7684;&#x51E0;&#x79CD;&#x6548;&#x5E94;&#x6B66;&#x5668;&#x4E4B;&#x4E00;&#x3002;&#x867D;&#x7136;&#x975E;&#x5E38;&#x5C11;&#x7684;&#x6076;&#x6027;&#x8868;&#x578B;&#x4EA7;&#x751F;&#x751F;&#x6B96;&#x6216;&#x6700;&#x591A;&#x4E94;&#x4E2A; FoxO &#x7B49;&#x4F4D;&#x57FA;&#x56E0;&#x7684;&#x4F53;&#x7EC6;&#x80DE;&#x5220;&#x9664;&#xFF0C;&#x6240;&#x6709; FoxOs &#x5E7F;&#x6CDB;&#x4F53;&#x7EC6;&#x80DE;&#x5220;&#x9664;&#x9020;&#x6210;&#x80F8;&#x817A;&#x6DCB;&#x5DF4;&#x7624;&#x548C;&#x8840;&#x7BA1;&#x7624;&#xFF0C;&#x8868;&#x660E;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x7684; FoxOs &#x786E;&#x5B9E;&#x771F;&#x6B63;&#x80BF;&#x7624;&#x6291;&#x5236;&#x5668;&#x7684;&#x7279;&#x70B9;&#x9010;&#x6B65;&#x5BB9;&#x6613;&#x53D1;&#x751F;&#x764C;&#x75C7;&#x7684;&#x6761;&#x4EF6;&#x3002;&#x5DEE;&#x5F02;&#x53D7;&#x5F71;&#x54CD;&#x7684;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x7684;&#x8F6C;&#x5F55;&#x8FC7;&#x7A0B;&#x548C;&#x542F;&#x52A8;&#x5B50;&#x5206;&#x6790;&#x786E;&#x5B9A;&#x4E86;&#x76F4;&#x63A5; FoxO &#x76EE;&#x6807;&#x548C;&#x63ED;&#x793A; FoxO &#x8C03;&#x8282;&#x4F53;&#x5185;&#x76EE;&#x6807;&#xFF0C;&#x8FD9;&#x4E9B;&#x76EE;&#x6807;&#x662F;&#x975E;&#x5E38;&#x5177;&#x4F53;&#x7684;&#x5373;&#x4F7F;&#x5728;&#x76F8;&#x540C;&#x7684;&#x5355;&#x5143;&#x683C;&#x7C7B;&#x578B;&#x3002;&#x529F;&#x80FD;&#x7814;&#x7A76;&#x9A8C;&#x8BC1;&#x4E86; Sprouty2 &#x548C; PBX1&#xFF0C;&#x9664;&#x5176;&#x4ED6;&#x5916;&#xFF0C;FoxO &#x8C03;&#x8282;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x5F62;&#x6001;&#x548C;&#x8840;&#x7BA1;&#x7A33;&#x6001;&#x7684;&#x8C03;&#x89E3;&#x8005;&#x3002;

FoxOs &#x662F;&#x6CBF;&#x88AD;&#x9650;&#x5236;&#x5197;&#x4F59;&#x80BF;&#x7624;&#x6291;&#x5236;&#x548C;&#x8C03;&#x8282;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x52A8;&#x6001;&#x5E73;&#x8861;&#x3002;

Activated phosphoinositide 3-kinase (PI3K)-AKT signaling appears to be an obligate event in the development of cancer. The highly related members of the mammalian FoxO transcription factor family, FoxO1, FoxO3, and FoxO4, represent one of several effector arms of PI3K-AKT signaling, prompting genetic analysis of the role of FoxOs in the neoplastic phenotypes linked to PI3K-AKT activation. While germline or somatic deletion of up to five FoxO alleles produced remarkably modest neoplastic phenotypes, broad somatic deletion of all FoxOs engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas, demonstrating that the mammalian FoxOs are indeed bona fide tumor suppressors. Transcriptome and promoter analyses of differentially affected endothelium identified direct FoxO targets and revealed that FoxO regulation of these targets in vivo is highly context-specific, even in the same cell type. Functional studies validated Sprouty2 and PBX1, among others, as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.

FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis.

Activated phosphoinositide 3-kinase (PI3K)-AKT signalisation semble &#xEA;tre un &#xE9;v&#xE9;nement obligatoire dans le d&#xE9;veloppement du cancer. Les membres hautement apparent&#xE9;s de la famille des mammif&#xE8;res FoxO facteur de transcription, FOXO1, FOXO3, et FoxO4, repr&#xE9;sentent l&#x26;#39;un des nombreux bras effectrices de signalisation PI3K-AKT, ce qui incite l&#x26;#39;analyse g&#xE9;n&#xE9;tique du r&#xF4;le de la FoxOs dans les ph&#xE9;notypes n&#xE9;oplasiques li&#xE9;s &#xE0; l&#x26;#39;activation PI3K-AKT. Alors que la suppression de lign&#xE9;e germinale ou somatique pouvant aller jusqu&#x26;#39;&#xE0; cinq all&#xE8;les FOXO produit remarquablement modeste ph&#xE9;notypes n&#xE9;oplasiques, large d&#xE9;l&#xE9;tion somatique de tous les FoxOs engendr&#xE9; une progressive pr&#xE9;dispos&#xE9;e au cancer &#xE9;tat caract&#xE9;ris&#xE9; par des lymphomes thymiques et les h&#xE9;mangiomes, d&#xE9;montrant que les FoxOs mammif&#xE8;res sont en effet de bonne foi des suppresseurs de tumeurs. Transcriptome et l&#x26;#39;analyse du promoteur de l&#x26;#39;endoth&#xE9;lium affect&#xE9;s diff&#xE9;remment identifi&#xE9;s directs objectifs FOXO et a r&#xE9;v&#xE9;l&#xE9; que la r&#xE9;glementation FoxO de ces objectifs in vivo est tr&#xE8;s sp&#xE9;cifique au contexte, m&#xEA;me dans le m&#xEA;me type de cellule. Les &#xE9;tudes fonctionnelles valid&#xE9;es Sprouty2 et PBX1, entre autres, que FoxO r&#xE9;glement&#xE9;s m&#xE9;diateurs de la morphogen&#xE8;se des cellules endoth&#xE9;liales et l&#x26;#39;hom&#xE9;ostasie vasculaire.

Etes-FoxOs Lineage restreints suppresseurs de tumeurs redondantes et r&#xE9;gulent l&#x26;#39;hom&#xE9;ostasie des cellules endoth&#xE9;liales

Attivato fosfoinositide 3-chinasi (PI3K)-segnalazione di AKT sembra essere un evento obligato nello sviluppo del cancro. I membri altamente correlati i mammiferi FoxO famiglia di fattore di trascrizione FoxO1, FoxO3 e FoxO4, rappresentano uno dei diversi rami effettrici di PI3K-AKT signaling, spingendo l&#39;analisi genetica del ruolo di FoxOs nei fenotipi neoplastici legata all&#39;attivazione di PI3K-AKT. Mentre germinale o somatico eliminazione degli alleli FoxO fino a cinque prodotti notevolmente modesti fenotipi neoplastici, ampia delezione somatica di FoxOs tutte le gener&ograve; una condizione soggetta a cancro progressiva caratterizzata da linfomi timici ed emangiomi, dimostrando che il FoxOs dei mammiferi sono soppressori tumorali infatti bona fide. Analisi transcriptome e promotore dell&#39;endotelio differenzialmente interessato identificato diretti FoxO obiettivi e ha rivelato che FoxO regolamento di questi obiettivi in vivo &egrave; altamente specifici per il contesto, anche nello stesso tipo di cellula. Studi funzionali convalidati Sprouty2 e PBX1, tra gli altri, come regolamentato FoxO mediatori della morfogenesi delle cellule endoteliali e omeostasi vascolare.

FoxOs sono soppressori tumorali ridondante limitato di lignaggio e regolano l&#39;omeostasi delle cellule endoteliali.

&#x6D3B;&#x6027;&#x5316;&#x3055;&#x308C;&#x305F;&#x30DB;&#x30B9;&#x30DB;&#x30A4;&#x30CE;&#x30B7;&#x30C1;&#x30C9;3  - &#x30AD;&#x30CA;&#x30FC;&#x30BC;&#xFF08;PI3K&#xFF09;-AKT&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306F;&#x3001;&#x764C;&#x306E;&#x958B;&#x767A;&#x306B;&#x7D76;&#x5BFE;&#x7684;&#x30A4;&#x30D9;&#x30F3;&#x30C8;&#x3067;&#x3042;&#x308B;&#x3088;&#x3046;&#x306B;&#x898B;&#x3048;&#x307E;&#x3059;&#x3002;&#x54FA;&#x4E73;&#x985E;&#x306E;FOXO&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x30D5;&#x30A1;&#x30DF;&#x30EA;&#x30FC;&#x3001;FOXO1&#x3001;FoxO3&#x3001;&#x3068;FoxO4&#x306E;&#x95A2;&#x9023;&#x6027;&#x306E;&#x9AD8;&#x3044;&#x30E1;&#x30F3;&#x30D0;&#x30FC;&#x306F;&#x3001;PI3K-AKT&#x306E;&#x6D3B;&#x6027;&#x5316;&#x306B;&#x30EA;&#x30F3;&#x30AF;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x816B;&#x760D;&#x8868;&#x73FE;&#x578B;&#x306E;FoxOs&#x306E;&#x5F79;&#x5272;&#x306E;&#x907A;&#x4F1D;&#x5B66;&#x7684;&#x89E3;&#x6790;&#x3092;&#x4FC3;&#x3057;&#x3001;PI3K-AKT&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x306E;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x30A8;&#x30D5;&#x30A7;&#x30AF;&#x30BF;&#x30FC;&#x306E;&#x8155;&#x306E;&#x3044;&#x305A;&#x308C;&#x304B;&#x3092;&#x8868;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002; 5 FOXO&#x306E;&#x5BFE;&#x7ACB;&#x307E;&#x3067;&#x306E;&#x751F;&#x6B96;&#x7D30;&#x80DE;&#x307E;&#x305F;&#x306F;&#x4F53;&#x306E;&#x6B20;&#x5931;&#x306F;&#x3001;&#x54FA;&#x4E73;&#x52D5;&#x7269;&#x306E;FoxOs&#x304C;&#x672C;&#x5F53;&#x306B;&#x5584;&#x610F;&#x306E;&#x816B;&#x760D;&#x6291;&#x5236;&#x56E0;&#x5B50;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x8A3C;&#x660E;&#x3059;&#x308B;&#x975E;&#x5E38;&#x306B;&#x63A7;&#x3048;&#x3081;&#x306A;&#x816B;&#x760D;&#x306E;&#x8868;&#x73FE;&#x578B;&#x3001;&#x80F8;&#x817A;&#x30EA;&#x30F3;&#x30D1;&#x816B;&#x304A;&#x3088;&#x3073;&#x8840;&#x7BA1;&#x816B;&#x304C;&#x7279;&#x5FB4;&#x9032;&#x884C;&#x764C;&#x304C;&#x767A;&#x751F;&#x3057;&#x3084;&#x3059;&#x3044;&#x72B6;&#x614B;&#x3092;&#x751F;&#x307F;&#x51FA;&#x3057;&#x3001;&#x3059;&#x3079;&#x3066;&#x306E;FoxOs&#x306E;&#x5E83;&#x3044;&#x4F53;&#x6B20;&#x5931;&#x3092;&#x3001;&#x751F;&#x7523;&#x3057;&#x306A;&#x304C;&#x3089;&#x3002;&#x5DEE;&#x306E;&#x5F71;&#x97FF;&#x3092;&#x53D7;&#x3051;&#x308B;&#x5185;&#x76AE;&#x76F4;&#x63A5;FOXO&#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3092;&#x540C;&#x5B9A;&#x3057;&#x3001;in vivo&#x3067;&#x306E;&#x3053;&#x308C;&#x3089;&#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x306E;FOXO&#x306E;&#x898F;&#x5236;&#x3082;&#x540C;&#x3058;&#x7D30;&#x80DE;&#x578B;&#x3067;&#x3001;&#x9AD8;&#x5EA6;&#x306B;&#x30B3;&#x30F3;&#x30C6;&#x30AD;&#x30B9;&#x30C8;&#x56FA;&#x6709;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x305F;&#x306E;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30AF;&#x30EA;&#x30D7;&#x30C8;&#x30FC;&#x30E0;&#x304A;&#x3088;&#x3073;&#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x89E3;&#x6790;&#x3002;&#x6A5F;&#x80FD;&#x7684;&#x306A;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x306E;&#x5F62;&#x614B;&#x5F62;&#x6210;&#x3001;&#x8840;&#x7BA1;&#x306E;&#x6052;&#x5E38;&#x6027;&#x306E;FOXO&#x8ABF;&#x7BC0;&#x30E1;&#x30C7;&#x30A3;&#x30A8;&#x30FC;&#x30BF;&#x30FC;&#x3068;&#x3057;&#x3066;&#x3001;&#x3068;&#x308A;&#x308F;&#x3051;&#x3001;Sprouty2&#x3068;PBX1&#x3092;&#x691C;&#x8A3C;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;

FoxOs&#x306F;&#x30EA;&#x30CD;&#x30FC;&#x30B8;&#x30E5;&#x5236;&#x9650;&#x3055;&#x308C;&#x305F;&#x5197;&#x9577;&#x306A;&#x816B;&#x760D;&#x6291;&#x5236;&#x56E0;&#x5B50;&#x3067;&#x3001;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x306E;&#x6052;&#x5E38;&#x6027;&#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;

Phosphoinositide 3-&#xD0A4; &#xB2C8; &#xC544; &#xC81C; (PI3K) &#xD65C;&#xC131;&#xD654;-AKT &#xC2DC;&#xADF8;&#xB110;&#xB9C1; &#xC554; &#xAC1C;&#xBC1C;&#xC5D0;&#xC11C; &#xC758;&#xBB34; &#xC774;&#xBCA4;&#xD2B8; &#xB098;&#xD0C0;&#xB0A9;&#xB2C8;&#xB2E4;. &#xD3EC;&#xC720;&#xB958; FoxO &#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778; &#xAC00;&#xC871;, FoxO1, FoxO3, &#xBC0F; FoxO4, &#xB192;&#xAC8C; &#xAD00;&#xB828;&#xB41C; &#xD68C;&#xC6D0; PI3K AKT &#xC2E0;&#xD638;, PI3K AKT &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xC5F0;&#xACB0; &#xB77C;&#xB294; &#xC885;&#xC591; &#xC57D; &#xACE0;&#xAE30;&#xC5D0; Foxos&#xC758; &#xC5ED;&#xD560;&#xC758; &#xC720;&#xC804;&#xC790; &#xBD84;&#xC11D;&#xC758; &#xC5EC;&#xB7EC; &#xC774;&#xD399;&#xD130; &#xBB34;&#xAE30; &#xC911; &#xD558;&#xB098;&#xB97C; &#xB098;&#xD0C0;&#xB0C5;&#xB2C8;&#xB2E4;. &#xBC88;&#xC9F8; &#xB610;&#xB294; &#xCD5C;&#xB300; 5 &#xAC1C;&#xC758; FoxO &#xB300;&#xB9BD; &#xCCB4;&#xC138;&#xD3EC; &#xC0AD;&#xC81C; &#xB108;&#xBB34;&#xB098; &#xACB8;&#xC190; &#xD55C; &#xC885;&#xC591; &#xC57D; &#xACE0;&#xAE30;, &#xC81C;&#xC791; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xBAA8;&#xB4E0; Foxos&#xC758; &#xAD11;&#xBC94;&#xC704; &#xD55C; &#xCCB4;&#xC138;&#xD3EC; &#xC0AD;&#xC81C; &#xC9C4;&#xBCF4;&#xC801;&#xC778; &#xC554; &#xBC1C;&#xC0DD; &#xD558;&#xAE30; &#xC26C;&#xC6B4; &#xC870;&#xAC74;&#xC744; thymic lymphomas&#xACFC; hemangiomas, &#xD3EC;&#xC720;&#xB958; Foxos&#xB294; &#xCC38;&#xC73C;&#xB85C; &#xD0C0;&#xACE0; &#xB09C; &#xC885;&#xC591; &#xC9C4;&#xC555;&#xC744; &#xBCF4;&#xC5EC;&#xC8FC;&#xB294; &#xD2B9;&#xC9D5;&#xC744; &#xBC1C;&#xC0DD; &#xC2DC;&#xCF30;&#xB2E4;. &#xCC28;&#xB3D9; &#xC601;&#xD5A5;&#xC744; &#xBC1B;&#xB294; &#xD53C; &#xB0B4; &#xB9C9;&#xC758; Transcriptome &#xBC0F; &#xD504;&#xB85C;&#xBAA8;&#xD130; &#xBD84;&#xC11D; &#xC9C1;&#xC811; FoxO &#xB300;&#xC0C1; &#xC2DD;&#xBCC4; &#xD558; &#xACE0; &#xC774;&#xB7EC;&#xD55C; &#xB300;&#xC0C1; &#xC0DD;&#xCCB4; &#xC870;&#xAC74; FoxO &#xADDC;&#xC81C;&#xB294; &#xB9E4;&#xC6B0; &#xB9DE;&#xB294;, &#xB3D9;&#xC77C;&#xD55C; &#xC140; &#xC720;&#xD615; &#xC5D0;&#xC11C;&#xB3C4; &#xBC1D;&#xD600;. &#xAE30;&#xB2A5;&#xC131; &#xC5F0;&#xAD6C; morphogenesis &#xB0B4; &#xD53C; &#xC138;&#xD3EC;&#xC640; &#xD608;&#xAD00; &#xD56D;&#xC0C1;&#xC131; FoxO &#xADDC;&#xC81C; &#xC911;&#xC7AC;&#xC790;&#xB85C;, Sprouty2 &#xBC0F; PBX1&#xB97C; &#xD655;&#xC778;.

Foxos&#xB294; &#xC911;&#xBCF5; &#xC885;&#xC591; &#xD608;&#xD1B5; &#xC81C;&#xD55C; &#xC9C4;&#xC555; &#xBC0F; &#xB0B4; &#xD53C; &#xC138;&#xD3EC; &#xD56D;&#xC0C1;&#xC131; &#xC870;&#xC808;.

Activado phosphoinositide 3-kinasa (PI3K)-AKT se&#xF1;alizaci&#xF3;n parece ser un evento obligado para el desarrollo de c&#xE1;ncer. Los miembros altamente relacionados de la familia del factor de transcripci&#xF3;n de los mam&#xED;feros FoxO, FoxO1, FoxO3 y FoxO4, representan uno de los varios brazos efectores de la PI3K-AKT se&#xF1;alizaci&#xF3;n, lo que provoc&#xF3; el an&#xE1;lisis gen&#xE9;tico de la funci&#xF3;n de Foxos en los fenotipos neopl&#xE1;sicos relacionados con la activaci&#xF3;n de la PI3K-AKT. Si bien la eliminaci&#xF3;n de l&#xED;nea germinal o som&#xE1;tica de un m&#xE1;ximo de cinco alelos FoxO producido fenotipos neopl&#xE1;sicos muy modestos, amplia eliminaci&#xF3;n de todas las som&#xE1;tica Foxos engendr&#xF3; una progresiva propensa al c&#xE1;ncer enfermedad que se caracteriza por linfomas t&#xED;micos y hemangiomas, lo que demuestra que los mam&#xED;feros son Foxos hecho de buena fe supresores de tumores. Transcriptoma y an&#xE1;lisis del promotor de endotelio diferencialmente afectados directos identificados los objetivos FoxO y revel&#xF3; que la regulaci&#xF3;n FoxO de estos objetivos en vivo es altamente espec&#xED;fica al contexto, incluso en el mismo tipo de c&#xE9;lulas. Los estudios funcionales validados Sprouty2 y PBX1, entre otros, como FoxO regulados por mediadores de la morfog&#xE9;nesis de c&#xE9;lulas endoteliales y la homeostasis vascular.

Foxos son linaje restringido Supresores de Tumor redundantes y regulaci&#xF3;n de la homeostasis de las c&#xE9;lulas endoteliales

Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53(-/-) Pten(-/-)) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53(-/-) Pten(-/-) TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.

p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation.

mTORC1 is a validated therapeutic target for renal cell carcinoma (RCC). Here, analysis of Tsc1-deficient (mTORC1 hyperactivation) mice uncovered a FoxO-dependent negative feedback circuit constraining mTORC1-mediated renal tumorigenesis. We document robust FoxO activation in Tsc1-deficient benign polycystic kidneys and FoxO extinction on progression to murine renal tumors; murine renal tumor progression on genetic deletion of both Tsc1 and FoxOs; and downregulated FoxO expression in most human renal clear cell and papillary carcinomas, yet continued expression in less aggressive RCCs and benign renal tumor subtypes. Mechanistically, integrated analyses revealed that FoxO-mediated block operates via suppression of Myc through upregulation of the Myc antagonists, Mxi1-SRα and mir-145, establishing a FoxO-Mxi1-SRα/mir-145 axis as a major progression block in renal tumor development.

FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis.

Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression. Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans.

SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression.

To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm(-/-) mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy.

Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer.

To determine the role of telomere dysfunction and telomerase reactivation in generating pro-oncogenic genomic events and in carcinoma progression, an inducible telomerase reverse transcriptase (mTert) allele was crossed onto a prostate cancer-prone mouse model null for Pten and p53 tumor suppressors. Constitutive telomerase deficiency and associated telomere dysfunction constrained cancer progression. In contrast, telomerase reactivation in the setting of telomere dysfunction alleviated intratumoral DNA-damage signaling and generated aggressive cancers with rearranged genomes and new tumor biological properties (bone metastases). Comparative oncogenomic analysis revealed numerous recurrent amplifications and deletions of relevance to human prostate cancer. Murine tumors show enrichment of the TGF-β/SMAD4 network, and genetic validation studies confirmed the cooperative roles of Pten, p53, and Smad4 deficiencies in prostate cancer progression, including skeletal metastases. Thus, telomerase reactivation in tumor cells experiencing telomere dysfunction enables full malignant progression and provides a mechanism for acquisition of cancer-relevant genomic events endowing new tumor biological capabilities.

Zhihu Ding

Sanofi US

Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer