HOXB5 Cooperates with NKX2-1 in the Transcription of Human RET

被引:19
作者
Zhu, Jiang [1 ]
Garcia-Barcelo, Maria-Mercedes [1 ,2 ]
Tam, Paul Kwong Hang [1 ,2 ]
Lui, Vincent Chi Hang [1 ,2 ]
机构
[1] Univ Hong Kong, Dept Surg Dev & Growth, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China
[2] Univ Hong Kong, Ctr Reprod Dev & Growth, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China
来源
PLOS ONE | 2011年 / 6卷 / 06期
关键词
ENTERIC NERVOUS-SYSTEM; RNA-POLYMERASE-II; HIRSCHSPRUNGS-DISEASE; C-RET; PROTOONCOGENE PROMOTER; GENE-EXPRESSION; CORE PROMOTER; 2.1; PROTEIN; STEM-CELL; MUTATIONS;
D O I
10.1371/journal.pone.0020815
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The enteric nervous system (ENS) regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR) in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET) is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i) HOXB5 transcription factor mediates RET expression, and (ii) mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i) elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii) examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 59 upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297), which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype.
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页数:8
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