Inactivation of SMC2 shows a synergistic lethal response in MYCN-amplified neuroblastoma cells

被引：31

作者：

Murakami-Tonami, Yuko ^{[1
]}

Kishida, Satoshi ^{[1
]}

Takeuchi, Ichiro ^{[2
]}

Katou, Yuki ^{[3
]}

Maris, John M. ^{[4
,5
]}

Ichikawa, Hitoshi ^{[6
]}

Kondo, Yutaka ^{[7
,8
]}

Sekido, Yoshitaka ^{[7
]}

Shirahige, Katsuhiko ^{[3
]}

Murakami, Hiroshi ^{[9
]}

Kadomatsu, Kenji ^{[1
]}

机构：

[1] Nagoya Univ, Grad Sch Med, Dept Mol Biol, Nagoya, Aichi 4648601, Japan

[2] Nagoya Inst Technol, Dept Comp Sci Sci & Engn Simulat, Nagoya, Aichi, Japan

[3] Univ Tokyo, Inst Mol & Cellular Biosci, Lab Genome Struct & Funct, Tokyo, Japan

[4] Univ Penn, Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[5] Univ Penn, Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[6] Natl Canc Inst, Div Genet, Tokyo, Japan

[7] Aichi Canc Ctr, Res Inst, Div Mol Oncol, Nagoya, Aichi 464, Japan

[8] Aichi Canc Ctr, Res Inst, Div Epigen, Nagoya, Aichi 464, Japan

[9] Chuo Univ, Fac Sci & Engn, Dept Biol Sci, Tokyo 112, Japan

来源：

CELL CYCLE | 2014年 / 13卷 / 07期

关键词：

condensin complex; DNA damage response; MYCN; neuroblastoma; synergistic lethal response; C-MYC; DNA-DAMAGE; N-MYC; ACTIVATING MUTATIONS; THERAPEUTIC TARGET; ALK KINASE; CONDENSIN; PROTEIN; EXPRESSION; ONCOGENE;

D O I：

10.4161/cc.27983

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The condensin complex is required for chromosome condensation during mitosis; however, the role of this complex during interphase is unclear. Neuroblastoma is the most common extracranial solid tumor of childhood, and it is often lethal. In human neuroblastoma, MYCN gene amplification is correlated with poor prognosis. This study demonstrates that the gene encoding the condensin complex subunit SMC2 is transcriptionally regulated by MYCN. SMC2 also transcriptionally regulates DNA damage response genes in cooperation with MYCN. Downregulation of SMC2 induced DNA damage and showed a synergistic lethal response in MYCN-amplified/overexpression cells, leading to apoptosis in human neuroblastoma cells. Finally, this study found that patients bearing MYCN-amplified tumors showed improved survival when SMC2 expression was low. These results identify novel functions of SMC2 in DNA damage response, and we propose that SMC2 (or the condensin complex) is a novel molecular target for the treatment of MYCN-amplified neuroblastoma.

引用

页码：1115 / 1131

页数：17

共 59 条

[1] Opposing role of condensin hinge against replication protein A in mitosis and interphase through promoting DNA annealing
Akai, Yuko
Kurokawa, Yumiko
Nakazawa, Norihiko
Tonami-Murakami, Yuko
Suzuki, Yuki
Yoshimura, Shige H.
Iwasaki, Hiroshi
Shiroiwa, Yoshiharu
Nakamura, Takahiro
Shibata, Eri
Yanagida, Mitsuhiro
[J]. OPEN BIOLOGY, 2011, 1
[2] Misregulation of mitotic chromosome segregation in a new type of autosomal recessive primary microcephaly
Alberto Marchal, Juan
Ghani, Mahdi
Schindler, Detlev
Gavvovidis, Ioannis
Winkler, Tina
Esquitino, Veronique
Sternberg, Nadine
Busche, Andreas
Krawitz, Peter
Hecht, Joachim
Robinson, Peter
Mundlos, Stephan
Graul-Neumann, Luitgard
Sperling, Karl
Trimborn, Marc
Neitzel, Heidemarie
[J]. CELL CYCLE, 2011, 10 (17) : 2967 - 2977
[3] Cnd2 has dual roles in mitotic condensation and interphase
Aono, N
Sutani, T
Tomonaga, T
Mochida, S
Yanagida, M
[J]. NATURE, 2002, 417 (6885) : 197 - 202
[4] Basu A, 2010, J NUCL ACIDS, V2010, DOI [10.4061/2010/201367 20811617, DOI 10.4061/2010/20136720811617]
[5] N-MYC regulates focal adhesion kinase expression in human neuroblastoma
Beierle, Elizabeth A.
Trujillo, Angelica
Nagaram, Abhilasha
Kurenova, Elena V.
Finch, Richard
Ma, Xiaojie
Vella, Jennifer
Cance, William G.
Golubovskaya, Vita M.
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (17) : 12503 - 12516
[6] BINDING OF MYC PROTEINS TO CANONICAL AND NONCANONICAL DNA-SEQUENCES
BLACKWELL, TK
HUANG, J
MA, A
KRETZNER, L
ALT, FW
EISENMAN, RN
WEINTRAUB, H
[J]. MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (09) : 5216 - 5224
[7] OPINION γH2AX and cancer
Bonner, William M.
Redon, Christophe E.
Dickey, Jennifer S.
Nakamura, Asako J.
Sedelnikova, Olga A.
Solier, Stephanie
Pommier, Yves
[J]. NATURE REVIEWS CANCER, 2008, 8 (12) : 957 - 967
[8] Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Bryant, HE
Schultz, N
Thomas, HD
Parker, KM
Flower, D
Lopez, E
Kyle, S
Meuth, M
Curtin, NJ
Helleday, T
[J]. NATURE, 2005, 434 (7035) : 913 - 917
[9] Playing the End Game: DNA Double-Strand Break Repair Pathway Choice
Chapman, J. Ross
Taylor, Martin R. G.
Boulton, Simon J.
[J]. MOLECULAR CELL, 2012, 47 (04) : 497 - 510
[10] Cti1/C1D interacts with condensin SMC hinge and supports the DNA repair function of condensin
Chen, ES
Sutani, T
Yanagida, M
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (21) : 8078 - 8083

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