TY - JOUR
T1 - Positive auto-regulation of MYCN in human neuroblastoma
AU - Suenaga, Yusuke
AU - Kaneko, Yoshiki
AU - Matsumoto, Daisuke
AU - Hossain, Mohammad Shamim
AU - Ozaki, Toshinori
AU - Nakagawara, Akira
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid from the Ministry of Health, Labor and Welfare for Third Term Comprehensive Control Research for Cancer, a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan, a Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, grants from Uehara Memorial Foundation, a Global COE Program (Global Center for Education and Research in Immune System Regulation and Treatment), Graduate School of Medicine, Chiba University. The authors thank Ms. Mami Yamamoto for technical assistance and Dr. Kiyohiro Ando for valuable discussions.
PY - 2009/12/4
Y1 - 2009/12/4
N2 - MYCN oncogene is one of the most important regulators affecting the prognosis of neuroblastoma and is frequently amplified in the high-risk subsets. Despite its clinical significance, it remains unclear how the MYCN expression is regulated in human neuroblastomas. Here, we found the presence of a positive auto-regulatory mechanism of MYCN. Enforced expression of MYCN induced endogenous MYCN mRNA expression in SK-N-AS neuroblastoma cells with a single copy of MYCN gene. Luciferase reporter assay revealed that MYCN protein activates its own promoter activity in a dose-dependent manner and the downstream region relative to the transcription start sites is responsible for the activation. Furthermore, ChIP analysis showed that MYCN is directly recruited onto the intron 1 region of MYCN gene which contains two putative E-box sites. Intriguingly, in response to all-trans-retinoic acid (ATRA), MYCN was down-regulated in MYCN-amplified SK-N-BE neuroblastoma cells, and the recruitment of MYCN protein onto its own intron 1 region was reduced in association with an induction of neuronal differentiation. Collectively, our present results suggest that MYCN contributes to its own expression by forming a positive auto-regulatory loop in neuroblastoma cells.
AB - MYCN oncogene is one of the most important regulators affecting the prognosis of neuroblastoma and is frequently amplified in the high-risk subsets. Despite its clinical significance, it remains unclear how the MYCN expression is regulated in human neuroblastomas. Here, we found the presence of a positive auto-regulatory mechanism of MYCN. Enforced expression of MYCN induced endogenous MYCN mRNA expression in SK-N-AS neuroblastoma cells with a single copy of MYCN gene. Luciferase reporter assay revealed that MYCN protein activates its own promoter activity in a dose-dependent manner and the downstream region relative to the transcription start sites is responsible for the activation. Furthermore, ChIP analysis showed that MYCN is directly recruited onto the intron 1 region of MYCN gene which contains two putative E-box sites. Intriguingly, in response to all-trans-retinoic acid (ATRA), MYCN was down-regulated in MYCN-amplified SK-N-BE neuroblastoma cells, and the recruitment of MYCN protein onto its own intron 1 region was reduced in association with an induction of neuronal differentiation. Collectively, our present results suggest that MYCN contributes to its own expression by forming a positive auto-regulatory loop in neuroblastoma cells.
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U2 - 10.1016/j.bbrc.2009.09.044
DO - 10.1016/j.bbrc.2009.09.044
M3 - Article
C2 - 19766596
AN - SCOPUS:70349975704
SN - 0006-291X
VL - 390
SP - 21
EP - 26
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -