NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma.
NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma.
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DOI：
10.1186/2051-5960-2-39
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发表时间：
2014-04-07
影响因子：
7.1
通讯作者：
Grotzer MA
中科院分区：
文献类型：
--
作者：
Fiaschetti G;Schroeder C;Castelletti D;Arcaro A;Westermann F;Baumgartner M;Shalaby T;Grotzer MA
Medulloblastoma (MB), the most common pediatric malignant brain cancer, typically arises as pathological result of deregulated developmental pathways, including the NOTCH signaling cascade. Unlike the evidence supporting a role for NOTCH receptors in MB development, the pathological functions of NOTCH ligands remain largely unexplored. By examining the expression in large cohorts of MB primary tumors, and in established in vitro MB models, this research study demonstrates that MB cells bear abnormal levels of distinct NOTCH ligands. We explored the potential association between NOTCH ligands and the clinical outcome of MB patients, and investigated the rational of inhibiting NOTCH signaling by targeting specific ligands to ultimately provide therapeutic benefits in MB. The research revealed a significant over-expression of ligand JAG1 in the vast majority of MBs, and proved that JAG1 mediates pro-proliferative signals via activation of NOTCH2 receptor and induction of HES1 expression, thus representing an attractive therapeutic target. Furthermore, we could identify a clinically relevant association between ligand JAG2 and the oncogene MYC, specific for MYC-driven Group 3 MB cases. We describe for the first time a mechanistic link between the oncogene MYC and NOTCH pathway in MB, by identifying JAG2 as MYC target, and by showing that MB cells acquire induced expression of JAG2 through MYC-induced transcriptional activation. Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.
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影响因子：
64.8
作者：
Northcott PA;Shih DJ;Peacock J;Garzia L;Morrissy AS;Zichner T;Stütz AM;Korshunov A;Reimand J;Schumacher SE;Beroukhim R;Ellison DW;Marshall CR;Lionel AC;Mack S;Dubuc A;Yao Y;Ramaswamy V;Luu B;Rolider A;Cavalli FM;Wang X;Remke M;Wu X;Chiu RY;Chu A;Chuah E;Corbett RD;Hoad GR;Jackman SD;Li Y;Lo A;Mungall KL;Nip KM;Qian JQ;Raymond AG;Thiessen NT;Varhol RJ;Birol I;Moore RA;Mungall AJ;Holt R;Kawauchi D;Roussel MF;Kool M;Jones DT;Witt H;Fernandez-L A;Kenney AM;Wechsler-Reya RJ;Dirks P;Aviv T;Grajkowska WA;Perek-Polnik M;Haberler CC;Delattre O;Reynaud SS;Doz FF;Pernet-Fattet SS;Cho BK;Kim SK;Wang KC;Scheurlen W;Eberhart CG;Fèvre-Montange M;Jouvet A;Pollack IF;Fan X;Muraszko KM;Gillespie GY;Di Rocco C;Massimi L;Michiels EM;Kloosterhof NK;French PJ;Kros JM;Olson JM;Ellenbogen RG;Zitterbart K;Kren L;Thompson RC;Cooper MK;Lach B;McLendon RE;Bigner DD;Fontebasso A;Albrecht S;Jabado N;Lindsey JC;Bailey S;Gupta N;Weiss WA;Bognár L;Klekner A;Van Meter TE;Kumabe T;Tominaga T;Elbabaa SK;Leonard JR;Rubin JB;Liau LM;Van Meir EG;Fouladi M;Nakamura H;Cinalli G;Garami M;Hauser P;Saad AG;Iolascon A;Jung S;Carlotti CG;Vibhakar R;Ra YS;Robinson S;Zollo M;Faria CC;Chan JA;Levy ML;Sorensen PH;Meyerson M;Pomeroy SL;Cho YJ;Bader GD;Tabori U;Hawkins CE;Bouffet E;Scherer SW;Rutka JT;Malkin D;Clifford SC;Jones SJ;Korbel JO;Pfister SM;Marra MA;Taylor MD
通讯作者：
Taylor MD
DOI：
10.1038/nrg3272
发表时间：
2012-09
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
21.3
作者：
Ma, Li;Young, Jennifer;Prabhala, Harsha;Pan, Elizabeth;Mestdagh, Pieter;Muth, Daniel;Teruya-Feldstein, Julie;Reinhardt, Ferenc;Onder, Tamer T.;Valastyan, Scott;Westermann, Frank;Speleman, Frank;Vandesompele, Jo;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.
影响因子：
11.5
作者：
Nam, Do-Hyun;Jeon, Hye-Min;Park, Woong-Yang
通讯作者：
Park, Woong-Yang
影响因子：
7.3
作者：
Fattet, Sarah;Haberler, Christine;Delattre, Olivier
通讯作者：
Delattre, Olivier