Alternative titles; symbols
HGNC Approved Gene Symbol: CCN4
Cytogenetic location: 8q24.22 Genomic coordinates (GRCh38) : 8:133,191,039-133,231,690 (from NCBI)
WNT1 (164820) belongs to a family of cysteine-rich, glycosylated signaling proteins that mediate diverse developmental processes, such as control of cell proliferation, adhesion, cell polarity, and establishment of cell fates. WISP1 is induced by WNT1 and belongs to the CCN family, which includes connective tissue growth factor (CTGF; 121009), cysteine-rich-61 (CYR61; 602369), and nephroblastoma overexpressed (NOV; 164958) (Tanaka et al., 2001).
Wnt1 was identified as an oncogene activated by the insertion of mouse mammary tumor virus in virus-induced mammary adenocarcinomas. Although Wnt1 is not expressed in the normal mammary gland, expression of Wnt1 in transgenic mice causes mammary tumors. To identify downstream genes in the WNT signaling pathway that are relevant to the transformed cell phenotype, Pennica et al. (1998) used a PCR-based cDNA subtraction strategy, suppression subtractive hybridization. Pennica et al. (1998) reported the identification of 2 genes, WISP1 and WISP2 (603399), that were upregulated in the mouse mammary epithelial cell line transformed by Wnt1, but not by Wnt4 (603490). Together with a third related gene, WISP3 (603399), these proteins define a subfamily of the CTGF family. The WISP1 protein contains 367 amino acids. Mouse and human WISP1 proteins are 84% identical, and both have hydrophobic N-terminal signal sequences, 38 conserved cysteine residues, and 4 potential N-linked glycosylation sites. Alignment of the 3 human WISP proteins showed that WISP1 and WISP3 are most similar (42%), whereas WISP2 had 37% identity with WISP1 and 32% identity with WISP3.
Tanaka et al. (2001) used targeted differential displays to identify a novel variant of WISP1, designated WISP1v, which was overexpressed in scirrhous gastric carcinomas. The predicted WISP1v protein completely lacks a module of von Willebrand factor type C (see 613160) that is thought to participate in protein complex formation.
Pennica et al. (1998) found that 2 distinct systems demonstrated that WISP induction was associated with expression of WNT1. WISP1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors, and its RNA was overexpressed in 84% of tumors examined compared with patient-matched normal mucosa. WISP3 also was overexpressed in 63% of colon tumors analyzed. In contrast, WISP2 showed reduced RNA expression in 79% of tumors. These results suggested that WISP genes may be downstream of WNT1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis.
Using Northern blot analysis, Xu et al. (2000) detected an increase in Wisp1 expression in mouse mammary epithelial cells expressing Wnt1 or stabilized beta-catenin (CTNNB1; 116806) mutants compared with parental cells. They cloned 5.9 kb of the WISP1 promoter and determined that WISP1 is a downstream target gene transcriptionally activated by WNT1 and CTNNB1 signaling. T-cell factor (TCF)-lymphoid enhancer factor (LEF; see 153245)-binding sites played a minor role, whereas the CREB site played an important role in this transcriptional activation. Overexpression of WISP1 in normal rat kidney fibroblast cells resulted in morphologic transformation and growth rate acceleration. Additionally, these cells formed WISP1-expressing tumors in nude mice. Xu et al. (2000) hypothesized that WISP1 may contribute to CTNNB1-mediated tumorigenesis and that elevated WISP1 expression in human colon adenocarcinomas could be the result of enhanced CTNNB1-mediated transcription.
Tanaka et al. (2001) found that ectopic expression of WISP1v showed it to be a secreted oncoprotein that induced a striking cellular transformation and rapid piling-up growth. They noted that WISP1 transfectants enhanced the invasive phenotype of cocultured gastric carcinoma cells, while wildtype WISP1 had no such potential.
By use of radiation hybrid mapping panels, Pennica et al. (1998) mapped the 3 WISP genes. WISP1 was mapped to chromosome 8q24.1-q24.3, roughly 4 Mb distal to MYC (190080). WISP2 was mapped to chromosome 20q12-q13.1, and WISP3 to chromosome 6q22-q23.
Pennica, D., Swanson, T. A., Welsh, J. W., Roy, M. A., Lawrence, D. A., Lee, J., Brush, J., Taneyhill, L. A., Deuel, B., Lew, M., Watanabe, C., Cohen, R. L., Melhem, M. F., Finley, G. G., Quirke, P., Goddard, A. D., Hillan, K. J., Gurney, A. L., Botstein, D., Levine, A. J. 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. Proc. Nat. Acad. Sci. 95: 14717-14722, 1998. [PubMed: 9843955] [Full Text: https://doi.org/10.1073/pnas.95.25.14717]
Tanaka, S., Sugimachi, K., Saeki, H., Kinoshita, J., Ohga, T., Shimada, M., Maehara, Y., Sugimachi, K. A novel variant of WISP1 lacking a von Willebrand type C module overexpressed in scirrhous gastric carcinoma. Oncogene 20: 5525-5532, 2001. [PubMed: 11571650] [Full Text: https://doi.org/10.1038/sj.onc.1204723]
Xu, L., Corcoran, R. B., Welsh, J. W., Pennica, D., Levine, A. J. WISP-1 is a Wnt-1- and beta-catenin-responsive oncogene. Genes Dev. 14: 585-595, 2000. [PubMed: 10716946]