Alternative titles; symbols
HGNC Approved Gene Symbol: CCN3
Cytogenetic location: 8q24.12 Genomic coordinates (GRCh38): 8:119,416,446-119,424,434 (from NCBI)
CCN3 belongs to the CCN family of intercellular signaling proteins and functions as a negative regulator of bone regeneration (Matsushita et al., 2013).
Soret et al. (1989) and Joliot et al. (1992) identified in myeloblastosis-associated virus (MAV)-1-induced avian nephroblastoma, a model of Wilms tumor, a new protooncogene they called nov for nephroblastoma overexpressed gene. Martinerie and Perbal (1991) found that human sequences homologous to nov were expressed in normal hematopoietic cells and in 1 nephroblastoma.
Snaith et al. (1996) stated that the NOV gene encodes a cysteine-rich protein that is overexpressed in avian nephroblastomas. It is a member of the CCN family of proteins that includes connective tissue growth factor (121009). These proteins are encoded by a group of genes known as immediate-early genes, so named because they are expressed after induction by growth factors or certain oncogenes. The proteins share several common structural motifs: a consensus sequence present in IGF (insulin-like growth factor)-binding proteins (the IGFBP motif), an oligomeric complex-forming domain first identified in von Willebrand factor (VWF; 613160), a binding domain to soluble and matrix molecules, and a dimerization (CT) domain (Bork, 1993). All CCN family members are thought to be involved in the control of cell proliferation. Snaith et al. (1996) isolated and characterized genomic and cDNA clones encompassing the mouse nov gene. It is highly conserved with the human and chick nov genes at the level of nucleotide sequence and genomic organization.
Using immunohistochemical analysis, Shimoyama et al. (2010) showed that Ccn3 localized in the medial layer of mouse aorta and colocalized with anti-alpha smooth muscle actin-positive cells. RT-PCR revealed that mouse Ccn3 was also expressed highly in heart and weakly in brain, lung, and muscle, with no expression in spleen and intestine.
Snaith et al. (1996) determined that the exon structure reflected the modular organization of NOV protein in a number of structural domains. These are highly conserved with other members of the CCN family, as is the distribution of 38 of its 40 cysteine residues.
By a combination of study of somatic cell hybrids and in situ hybridization, Martinerie et al. (1992) showed that the human NOV gene maps to 8q24.1, proximal to MYC (190080).
Snaith et al. (1996) mapped the nov gene to mouse chromosome 15 in a region of conserved synteny with human chromosome 8.
Kim et al. (1997) noted that NOV and the products of the other immediate-early genes CTGF (121009) and Cyr61 (602369) have significant sequence homology to the IGFBPs (see IGFBP7, 602867). They proposed that, together with IGFBP7, these proteins constitute a family of IGFBPs that bind IGFs with low affinity.
Thibout et al. (2003) developed an enzyme immunoassay specific for NOV and showed for the first time that the concentration of NOV differs in serum, urine, and cerebrospinal and amniotic fluids. The normal concentration of NOV circulating in the blood is 350 to 400 ng/ml, but this concentration varies with age. By using sera from patients with adrenal gland diseases, the authors found that in vivo ACTH or glucocorticoids are not responsible for the high concentration of NOV in this endocrine gland. However, the NOV concentration was significantly modified in malignant adrenocortical tumors, but not in benign adrenocortical tumors. The concentration of NOV was significantly decreased in patients suffering from astrocytomas or multiple sclerosis, 2 diseases of the nervous system. The authors concluded that NOV is a potentially useful marker for the diagnosis of these diseases.
Gupta et al. (2007) identified the matricellular protein Nov (CCN3) as being essential for the functional integrity of hematopoietic stem and progenitor cells. Nov expression is restricted to the primitive (CD34+; 142230) compartments of umbilical vein cord blood, and its knockdown in these cells by lentivirus-mediated RNA interference abrogates their function in vitro and in vivo. Conversely, forced expression of Nov and addition of recombinant Nov protein both enhanced primitive stem and/or progenitor activity. Taken together, Gupta et al. (2007) concluded that their results identified Nov as a regulator of human hematopoietic stem or progenitor cells.
Doghman et al. (2007) measured NOV protein levels in childhood adrenocortical tumors (ACTs) and characterized NOV expression, regulation, and biologic function in human adrenocortical cells. NOV mRNA and protein expression was lower in childhood ACTs than in normal adrenal cortex. No significant difference was observed between adenomas and carcinomas. Doghman et al. (2007) concluded that reduced expression of NOV in ACTs may play an important role in the process of childhood ACT tumorigenesis, accounting at least in part for the defect of apoptotic regression of the fetal adrenal that has been proposed to be responsible for tumor formation.
Using cultured rat vascular smooth muscle cells (VSMCs), Shimoyama et al. (2010) showed that Ccn3 inhibited VSMC proliferation independently of Tgf-beta (190180) signaling by upregulating expression of the cell cycle regulators p15 (CDKN2B; 600431) and p21 (CDKN1A; 116899) through the Notch (see 190198) signaling pathway. Additionally, Ccn3 inhibited VSMC migration in a dose-dependent manner.
Shimoyama et al. (2010) found that Ccn3 -/- mice were born at the expected mendelian frequency, were viable, and showed normal development and fertility. Body weight, systolic blood pressure, plasma glucose concentrations, and HbA1c levels were comparable between Ccn3 -/- and wildtype mice. Ccn3 -/- mice had normally developed vasculature and normal amount of extracellular matrix. However, Ccn3 -/- mice exhibited markedly enhanced neointimal thickening in response to injury compared with wildtype. VSMC proliferation was normal after vascular injury, but endothelialization was reduced in aortas of Ccn3 -/- mice.
Using microarray analysis, Matsushita et al. (2013) demonstrated that Ccn3 expression was upregulated at the early phase of bone regeneration in wildtype mice. Transgenic mice overexpressing Ccn3 exhibited less-active bone formation and osteopenia compared with wildtype, probably due to disturbance in differentiation and function of osteoblastic cells. Ccn3-knockout mice were fertile and appeared normal, with no apparent skeletal changes. Tomography and histologic analysis revealed accelerated bone regeneration in Ccn3-knockout mice, with highly upregulated phosphorylation of Smad1 (601595)/Smad5 (603110) at bone regeneration sites, compared with wildtype. In contrast, Ccn3 transgenic mice showed no significant changes in bone regeneration. The authors concluded that CCN3 is a negative regulator of bone regeneration.
Bork, P. The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett. 327: 125-130, 1993. [PubMed: 7687569] [Full Text: https://doi.org/10.1016/0014-5793(93)80155-n]
Doghman, M., Arhatte, M., Thibout, H., Rodrigues, G., De Moura, J., Grosso, S., West, A. N., Laurent, M., Mas, J.-C., Bongain, A., Zambetti, G. P., Figueiredo, B. C., Auberger, P., Martinerie, C., Lalli, E. Nephroblastoma overexpressed/cysteine-rich protein 61/connective tissue growth factor/nephroblastoma overexpressed gene-3 (NOV/CCN3), a selective adrenocortical cell preapoptotic factor, is down-regulated in childhood adrenocortical tumors. J. Clin. Endocr. Metab. 92: 3253-3260, 2007. [PubMed: 17566092] [Full Text: https://doi.org/10.1210/jc.2007-0342]
Gupta, R., Hong, D., Iborra, F., Sarno, S., Enver, T. NOV (CCN3) functions as a regulator of human hematopoietic stem or progenitor cells. Science 316: 590-593, 2007. [PubMed: 17463287] [Full Text: https://doi.org/10.1126/science.1136031]
Joliot, V., Martinerie, C., Dambrine, G., Plassiart, G., Brisac, M., Crochet, J., Perbal, B. Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. Molec. Cell. Biol. 12: 10-21, 1992. [PubMed: 1309586] [Full Text: https://doi.org/10.1128/mcb.12.1.10-21.1992]
Kim, H.-S., Nagalla, S. R., Oh, Y., Wilson, E., Roberts, C. T., Jr., Rosenfeld, R. G. Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc. Nat. Acad. Sci. 94: 12981-12986, 1997. [PubMed: 9371786] [Full Text: https://doi.org/10.1073/pnas.94.24.12981]
Martinerie, C., Perbal, B. Expression of a gene encoding a novel potential IGF binding protein in human tissues. C. R. Acad. Sci. (Paris) 313 (ser. 3): 345-351, 1991. [PubMed: 1756408]
Martinerie, C., Viegas-Pequignot, E., Guenard, I., Dutrillaux, B., Nguyen, V. C., Bernheim, A., Perbal, B. Physical mapping of human loci homologous to the chicken nov proto-oncogene. Oncogene 7: 2529-2534, 1992. [PubMed: 1334251]
Matsushita, Y., Sakamoto, K., Tamamura, Y., Shibata, Y., Minamizato, T., Kihara, T., Ito, M., Katsube, K., Hiraoka, S., Koseki, H., Harada, K., Yamaguchi, A. CCN3 protein participates in bone regeneration as an inhibitory factor. J. Biol. Chem. 288: 19973-19985, 2013. [PubMed: 23653360] [Full Text: https://doi.org/10.1074/jbc.M113.454652]
Shimoyama, T., Hiraoka, S., Takemoto, M., Koshizaka, M., Tokuyama, H., Tokuyama, T., Watanabe, A., Fujimoto, M., Kawamura, H., Sato, S., Tsurutani, Y., Saito, Y., Perbal, B., Koseki, H., Yokote, K. CCN3 inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration. Arterioscler. Thromb. Vasc. Biol. 30: 675-682, 2010. [PubMed: 20139355] [Full Text: https://doi.org/10.1161/ATVBAHA.110.203356]
Snaith, M. R., Natarajan, D., Taylor, L. B., Choi, C.-P., Martinerie, C., Perbal, B., Schofield, P. N., Boulter, C. A. Genomic structure and chromosomal mapping of the mouse nov gene. Genomics 38: 425-428, 1996. [PubMed: 8975721] [Full Text: https://doi.org/10.1006/geno.1996.0647]
Soret, J., Dambrine, G., Perbal, B. Induction of nephroblastoma by myeloblastosis-associated virus type 1: state of proviral DNAs in tumor cells. J. Virol. 63: 1803-1807, 1989. [PubMed: 2564440] [Full Text: https://doi.org/10.1128/JVI.63.4.1803-1807.1989]
Thibout, H., Martinerie, C., Creminon, C., Godeau, F., Boudou, P., Le Bouc, Y., Laurent, M. Characterization of human NOV in biological fluids: an enzyme immunoassay for the quantification of human NOV in sera from patients with diseases of the adrenal gland and of the nervous system. J. Clin. Endocr. Metab. 88: 327-336, 2003. [PubMed: 12519873] [Full Text: https://doi.org/10.1210/jc.2002-020304]