WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors
WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors
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DOI：
10.1073/pnas.95.25.14717
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发表时间：
1998-12-08
影响因子：
11.1
通讯作者：
Levine, AJ
中科院分区：
文献类型：
--
作者：
Pennica, D;Swanson, TA;Levine, AJ
Wnt 家族成员对许多发育过程至关重要，Wnt 信号通路的组成部分与家族性和散发性结肠癌的肿瘤发生有关。在这里，我们报告了两个基因 WISP-1 和 WISP-2 的鉴定，这两个基因在 Wnt-1 转化的小鼠乳腺上皮细胞系 C57MG 中上调，但 Wnt-4 转化的小鼠乳腺上皮细胞系 C57MG 中则上调。这些蛋白质与第三个相关基因 WISP-3 一起定义了结缔组织生长因子家族的一个亚家族。两个不同的系统证明 WISP 诱导与 Wnt-1 的表达相关。这些包括（i）用Wnt-1逆转录病毒载体感染或在四环素抑制启动子控制下表达Wnt-1的C57MG细胞，以及（ii）Wnt-1转基因小鼠。 WISP-1基因定位于人类染色体8q24.1-8q24.3。 WISP-1 基因组 DNA 在结肠癌细胞系和人类结肠肿瘤中扩增，与患者匹配的正常粘膜相比，其 RNA 在 84% 的检查肿瘤中过表达（2 至 >30 倍）。 WISP-3 定位于染色体 6q22-6q23，并且在所分析的 63% 的结肠肿瘤中也过表达（4 至 >40 倍）。相比之下，WISP-2 映射到人类染色体 20q12-20q13，其 DNA 被扩增，但在 79% 的肿瘤中 RNA 表达减少（2 至 >30 倍）。这些结果表明 WISP 基因可能位于 Wnt-1 信号传导的下游，并且结肠癌中 WISP 表达的异常水平可能在结肠肿瘤发生中发挥作用。
Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40 fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis.