Integrative genomic analyses on GLI2: Mechanism of Hedgehog priming through basal GLI2 expression, and interaction map of stem cell signaling network with P53
Integrative genomic analyses on GLI2: Mechanism of Hedgehog priming through basal GLI2 expression, and interaction map of stem cell signaling network with P53
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DOI：
10.3892/ijo_00000076
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发表时间：
2008-10-01
影响因子：
5.2
通讯作者：
Katoh, Masaru
中科院分区：
文献类型：
--
作者：
Katoh, Yuriko;Katoh, Masaru
Hedahog与Patched家族受体的结合导致Smoothened介导的MAP 3 K10（MST）活化和SUFU失活。MAP 3 K10诱导的DYRK 2磷酸化结合SUFU抑制导致GLI 2的稳定和核积累，用于GLI 1、CCND 1、CCND 2、FOXA 2、FOXC 2、FOXP 3、FOXQ 1、RUNX 2和JAG 2的转录激活。在此，对GLI 2直系同源物进行了整合基因组分析。通过组装外显子1、2和5 '-截短的大鼠Gli 2 RefSeq（NM_001107169.1）的核苷酸序列来确定大鼠Gli 2完整编码序列。GLI 2直系同源物与GLI 3直系同源物的相关性高于缺乏N-末端阻遏物结构域的GLI 1直系同源物。β BTRCP 1（FBXW 1）结合DSYxxxS基序在GLI 2和GLI 3直系同源物中是保守的，而β TRCP 2（FBXW 11）结合DSGxxxxxxxS基序在GLI 2和GLI 1直系同源物中是保守的。人GLI 2 mRNA在ES细胞、NT 2细胞、胎肺、胎心中均有表达。再生肝、胃癌和其他肿瘤。小鼠Gli 2 mRNA在未受精卵中表达。ES细胞。EG细胞。在GLI 2近端启动子区域内鉴定了P53、P63或P73的串联RRRCWWGYYY基序以及四个保守的bHL-结合位点。构建了P53与干细胞信号网络的相互作用图谱。P53诱导的NOTCH 1上调导致HES 1、HES 5、HEY 1、HEY 2或HEYL上调，以抑制组织特异性bHLH转录激活因子。DYRK 2作为P53介导的细胞凋亡的正调节剂，也作为Hedgehog信号级联的负调节剂。GLI 2表达基于P53、Notch和TGF-β信号传导以及Hedgehog信号传导激活的平衡来调节。
Hedaehog-binding to Patched family receptors results in Smoothened-mediated activation of MAP3K10 (MST) and inactivation of SUFU. MAP3K10-induced DYRK2 phosphorylation combined with SUFU inhibition results in the stabilization and nuclear accumulation of GLI2 for transcriptional activation of GLI1, CCND1, CCND2, FOXA2, FOXC2, FOXP3, FOXQ1, RUNX2, and JAG2. Here, integrative genomic analyses on GLI2 orthologs were carried out. Rat Gli2 complete coding sequence was determined by assembling nucleotide sequences of exons 1, 2, and 5'-truncated rat Gli2 RefSeq (NM_001107169.1). GLI2 orthologs were more related to GLI3 orthologs than to GLI1 orthologs lacking the N-terminal repressor domain. beta BTRCP1 (FBXW1)-binding DSYxxxS motif was conserved in GLI2 and GLI3 orthologs, while beta TRCP2 (FBXW11)-binding DSGxxxxxxxxxS motif in GLI2 and GLI1 orthologs. Human GLI2 mRNA was expressed in ES cells, NT2 cells, fetal lung, fetal heart. regenerating liver, gastric cancer, and other tumors. Mouse Gli2 mRNA was expressed in unfertilized egg. ES cells. and EG cells. Tandem RRRCWWGYYY motifs for P53, P63 or P73, and also four conserved bHLH-binding, sites were identified within GLI2 proximal promoter region. Interaction map of P53 and stem cell signaling network were then constructed. P53-induced NOTCH1 upregulation leads to HES1, HES5, HEY1, HEY2 or HEYL upregulation for the repression of tissue specific bHLH transcriptional activators. DYRK2 functions as a positive regulator of P53-mediated apoptosis, and also as a negative regulator of the Hedgehog signaling cascade. GLI2 expression is regulated based on the balance of P53, Notch, and TGF-beta signaling, and Hedgehog signaling activation