The Ewing's sarcoma oncoprotein EWS/FLI induces a p53-dependent growth arrest in primary human fibroblasts

被引:188
作者
Lessnick, SL
Dacwag, CS
Golub, TR [1 ]
机构
[1] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
[2] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA
[3] MIT, Whitehead Ctr Genome Res, Cambridge, MA 02142 USA
关键词
D O I
10.1016/S1535-6108(02)00056-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Ewing's sarcoma is associated with a fusion between the EWS and FLI1 genes, forming an EWS/FLI fusion protein. We developed a system for the identification of cooperative mutations in this tumor through expression of EWS/FLI in primary human fibroblasts. Gene expression profiling demonstrated that this system recapitulates many features of Ewing's sarcoma. EWS/FLI-expressing cells underwent growth arrest, suggesting that growth arrest-abrogating collaborative mutations may be required for tumorigenesis. Expression profiling identified transcriptional upregulation of p53, and the growth arrest was rescued by inhibition of p53. These data support a role for p53 as a tumor suppressor in Ewing's sarcoma and demonstrate the use of transcriptional profiling of model systems in the identification of cooperating mutations in human cancer.
引用
收藏
页码:393 / 401
页数:9
相关论文
共 38 条
[11]   Enumeration of the simian virus 40 early region elements necessary for human cell transformation [J].
Hahn, WC ;
Dessain, SK ;
Brooks, MW ;
King, JE ;
Elenbaas, B ;
Sabatini, DM ;
DeCaprio, JA ;
Weinberg, RA .
MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (07) :2111-2123
[12]   Mdm2 promotes the rapid degradation of p53 [J].
Haupt, Y ;
Maya, R ;
Kazaz, A ;
Oren, M .
NATURE, 1997, 387 (6630) :296-299
[13]   Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks [J].
Khan, J ;
Wei, JS ;
Ringnér, M ;
Saal, LH ;
Ladanyi, M ;
Westermann, F ;
Berthold, F ;
Schwab, M ;
Antonescu, CR ;
Peterson, C ;
Meltzer, PS .
NATURE MEDICINE, 2001, 7 (06) :673-679
[14]   Molecular genetics of chromosome translocations involving EWS and related family members [J].
Kim, J ;
Pelletier, J .
PHYSIOLOGICAL GENOMICS, 1999, 1 (03) :127-138
[15]   Among genes involved in the RB dependent cell cycle regulatory cascade, the p16 tumor suppressor gene is frequently lost in the Ewing family of tumors [J].
Kovar, H ;
Jug, G ;
Aryee, DNT ;
Zoubek, A ;
Ambros, P ;
Gruber, B ;
Windhager, R ;
Gadner, H .
ONCOGENE, 1997, 15 (18) :2225-2232
[16]  
KOVAR H, 1993, ONCOGENE, V8, P2683
[17]  
Kovar Heinrich, 1998, Current Opinion in Oncology, V10, P334, DOI 10.1097/00001622-199807000-00010
[18]   Regulation of p53 stability by Mdm2 [J].
Kubbutat, MHG ;
Jones, SN ;
Vousden, KH .
NATURE, 1997, 387 (6630) :299-303
[19]   MDM2 AND CDK4 GENE AMPLIFICATION IN EWINGS-SARCOMA [J].
LADANYI, M ;
LEWIS, R ;
JHANWAR, SC ;
GERALD, W ;
HUVOS, AG ;
HEALEY, JH .
JOURNAL OF PATHOLOGY, 1995, 175 (02) :211-217
[20]  
LESSNICK SL, 1995, ONCOGENE, V10, P423