Mutant p53 cooperates with ETS2 to promote etoposide resistance

被引:160
作者
Do, Phi M. [2 ]
Varanasi, Lakshman [2 ]
Fan, Songqing [1 ]
Li, Chunyang [1 ]
Kubacka, Iwona [3 ]
Newman, Virginia [2 ]
Chauhan, Krishna [2 ]
Daniels, Silvano Rakeem [2 ]
Boccetta, Maurizio [4 ]
Garrett, Michael R. [2 ]
Li, Runzhao [1 ]
Martinez, Luis A. [2 ]
机构
[1] Emory Univ, Sch Med, Dept Hematol & Med Oncol, Winship Canc Inst, Atlanta, GA 30322 USA
[2] Univ Mississippi, Med Ctr, Inst Canc, Dept Biochem, Jackson, MS 39216 USA
[3] Univ Texas Med Branch, Galveston, TX 77554 USA
[4] Loyola Univ Chicago, Inst Signal Transduct, Inst Oncol, Maywood, IL 60153 USA
基金
美国国家卫生研究院;
关键词
TDP2; cancer; p53; 5'-TYROSYL DNA PHOSPHODIESTERASE; TRANSCRIPTION FACTORS; LUNG-CANCER; GENE CONTRIBUTES; P73; FUNCTION; GAIN; PROTEIN; CELLS; BINDING; ACTIVATION;
D O I
10.1101/gad.181685.111
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Mutant p53 (mtp53) promotes chemotherapy resistance through multiple mechanisms, including disabling proapoptotic proteins and regulating gene expression. Comparison of genome wide analysis of mtp53 binding revealed that the ETS-binding site motif (EBS) is prevalent within predicted mtp53-binding sites. We demonstrate that mtp53 regulates gene expression through EBS in promoters and that ETS2 mediates the interaction with this motif. Importantly, we identified TDP2, a 5'-tyrosyl DNA phosphodiesterase involved in the repair of DNA damage caused by etoposide, as a transcriptional target of mtp53. We demonstrate that suppression of TDP2 sensitizes mtp53-expressing cells to etoposide and that mtp53 and TDP2 are frequently overexpressed in human lung cancer; thus, our analysis identifies a potentially "druggable'' component of mtp53's gain-of-function activity.
引用
收藏
页码:830 / 845
页数:16
相关论文
共 61 条
[1]   Development of a novel assay for human tyrosyl DNA phosphodiesterase 2 [J].
Adhikari, Sanjay ;
Karmahapatra, Soumendra K. ;
Elias, Hadi ;
Dhopeshwarkar, Priyanka ;
Williams, R. Scott ;
Byers, Stephen ;
Uren, Aykut ;
Roy, Rabindra .
ANALYTICAL BIOCHEMISTRY, 2011, 416 (01) :112-116
[2]   A Mutant-p53/Smad Complex Opposes p63 to Empower TGFβ-Induced Metastasis [J].
Adorno, Maddalena ;
Cordenonsi, Michelangelo ;
Montagner, Marco ;
Dupont, Sirio ;
Wong, Christine ;
Hann, Byron ;
Solari, Aldo ;
Bobisse, Sara ;
Rondina, Maria Beatrice ;
Guzzardo, Vincenza ;
Parenti, Anna R. ;
Rosato, Antonio ;
Bicciato, Silvio ;
Balmain, Allan ;
Piccolo, Stefano .
CELL, 2009, 137 (01) :87-98
[3]   Structural basis of Ets1 cooperative binding to palindromic sequences on stromelysin-1 promoter DNA [J].
Babayeva, Nigar D. ;
Wilder, Phillip J. ;
Shiina, Masaaki ;
Mino, Koshiki ;
Desler, Michelle ;
Ogata, Kazuhiro ;
Rizzino, Angie ;
Tahirov, Tahir H. .
CELL CYCLE, 2010, 9 (15) :3054-3062
[4]  
Bailey T L, 1994, Proc Int Conf Intell Syst Mol Biol, V2, P28
[5]   The Ets transcription factors interact with each other and with the c-Fos/c-Jun complex via distinct protein domains in a DNA-dependent and -independent manner [J].
Basuyaux, JP ;
Ferreira, E ;
Stehelin, D ;
Buttice, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (42) :26188-26195
[6]   p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis [J].
Bergamaschi, D ;
Gasco, M ;
Hiller, L ;
Sullivan, A ;
Syed, N ;
Trigiante, G ;
Yulug, I ;
Merlano, M ;
Numico, G ;
Comino, A ;
Attard, M ;
Reelfs, O ;
Gusterson, B ;
Bell, AK ;
Heath, V ;
Tavassoli, M ;
Farrell, PJ ;
Smith, P ;
Lu, X ;
Crook, T .
CANCER CELL, 2003, 3 (04) :387-402
[7]  
BISCHOFF FZ, 1990, CANCER RES, V50, P7979
[8]   Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy [J].
Blandino, G ;
Levine, AJ ;
Oren, M .
ONCOGENE, 1999, 18 (02) :477-485
[9]   Distinct p53 genomic binding patterns in normal and cancer-derived human cells [J].
Botcheva, Krassimira ;
McCorkle, Sean R. ;
McCombie, W. R. ;
Dunn, John J. ;
Anderson, Carl W. .
CELL CYCLE, 2011, 10 (24) :4237-4249
[10]   When mutants gain new powers: news from the mutant p53 field [J].
Brosh, Ran ;
Rotter, Varda .
NATURE REVIEWS CANCER, 2009, 9 (10) :701-713