WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene

被引:204
作者
Mayo, MW
Wang, CY
Drouin, SS
Madrid, LV
Marshall, AF
Reed, JC
Weissman, BE
Baldwin, AS [1 ]
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Sch Dent, Lab Mol Signaling & Apoptosis, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA
[5] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA
[6] Burnham Inst, La Jolla, CA 92037 USA
关键词
apoptosis; Bcl-2; transcriptional regulation; Wilms' tumor; WT1;
D O I
10.1093/emboj/18.14.3990
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Wilms' tumor suppressor gene, WT1, encodes a zinc finger transcription factor that has been demonstrated to negatively regulate several growth factor and cognate receptor genes. However, inconsistent with its tumor suppressor function, WT1 has also been demonstrated to be required to inhibit programmed cell death in vitro and in vivo. Moreover, anaplastic Wilms' tumors, which typically express wild-type WT1, display extreme resistance to chemotherapeutic agents that kill tumor cells through the induction of apoptosis, Although p53 mutations in anaplastic Wilms' tumors have been associated with chemoresistance, this event is believed to occur late during tumor progression. Therefore, since dysregulated WT1 expression occurs relatively early in Wilms' tumors, we hypothesized that WT1 was required to transcriptionally upregulate genes that provide a cell survival advantage to tumor cells. Here we demonstrate that sporadic Wilms' tumors coexpress WT1 and the anti-apoptotic Bcl-2 protein. Using rhabdoid cell lines overexpressing WT1, we show that WT1 activates the endogenous bcl-2 gene through a transcriptional mechanism. Transient transfections and electromobility shift assays demonstrate that WT1 positively stimulates the bcl-2 promoter through a direct interaction. Moreover, WT1 expressing cells displaying upregulated Bcl-2 were found to be resistant to apoptosis induced by staurosporine, vincristine and doxorubicine. These data suggest that in certain cellular contexts, WT1 exhibits oncogenic potential through the transcriptional upregulation of anti-apoptotic genes such as bcl-2.
引用
收藏
页码:3990 / 4003
页数:14
相关论文
共 79 条
[41]  
MADDEN SL, 1993, ONCOGENE, V8, P1713
[42]   TRANSCRIPTIONAL REPRESSION MEDIATED BY THE WT1 WILMS-TUMOR GENE-PRODUCT [J].
MADDEN, SL ;
COOK, DM ;
MORRIS, JF ;
GASHLER, A ;
SUKHATME, VP ;
RAUSCHER, FJ .
SCIENCE, 1991, 253 (5027) :1550-1553
[43]   Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70 [J].
Maheswaran, S ;
Englert, C ;
Zheng, G ;
Lee, SB ;
Wong, J ;
Harkin, DP ;
Bean, J ;
Ezzell, R ;
Garvin, AJ ;
McCluskey, RT ;
DeCaprio, JA ;
Haber, DA .
GENES & DEVELOPMENT, 1998, 12 (08) :1108-1120
[44]   THE WT1 GENE-PRODUCT STABILIZES P53 AND INHIBITS P53-MEDIATED APOPTOSIS [J].
MAHESWARAN, S ;
ENGLERT, C ;
BENNETT, P ;
HEINRICH, G ;
HABER, DA .
GENES & DEVELOPMENT, 1995, 9 (17) :2143-2156
[45]   PHYSICAL AND FUNCTIONAL INTERACTION BETWEEN WT1 AND P53 PROTEINS [J].
MAHESWARAN, S ;
PARK, S ;
BERNARD, A ;
MORRIS, JF ;
RAUSCHER, FJ ;
HILL, DE ;
HABER, DA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (11) :5100-5104
[46]   Requirement of NF-kappa B activation to suppress p53-independent apoptosis induced by oncogenic Ras [J].
Mayo, MW ;
Wang, CY ;
Cogswell, PC ;
RogersGraham, KS ;
Lowe, SW ;
Der, CJ ;
Baldwin, AS .
SCIENCE, 1997, 278 (5344) :1812-1815
[47]  
MCMASTER ML, 1995, CELL GROWTH DIFFER, V6, P1609
[48]  
MIYASHITA T, 1994, CANCER RES, V54, P3131
[49]  
NAKAGAMA H, 1995, MOL CELL BIOL, V15, P1489
[50]   TARGETED DISRUPTION OF BCL-2-ALPHA-BETA IN MICE - OCCURRENCE OF GRAY HAIR, POLYCYSTIC KIDNEY-DISEASE, AND LYMPHOCYTOPENIA [J].
NAKAYAMA, K ;
NAKAYAMA, K ;
NEGISHI, I ;
KUIDA, K ;
SAWA, H ;
LOH, DY .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (09) :3700-3704