NOV (gene)

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SpeciesHumanMouse
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NOV (nephroblastoma overexpressed) also known as CCN3 is a matricellular protein that in humans is encoded by the NOV gene.[1][2]

CCN family

NOV is a member of the CCN family of secreted, extracellular matrix (ECM)-associated signaling proteins (see also CCN intercellular signaling protein).[3][4] The CCN acronym is derived from the first three members of the family being identified, namely CYR61 (cysteine-rich angiogenic inducer 61, or CCN1), CTGF (connective tissue growth factor, or CCN2), and NOV. These proteins, together with WISP1 (CCN4), WISP2 (CCN5), and WISP3 (CCN6) comprise the six-member CCN family in vertebrates and have been renamed CCN1-6 in the order of their discovery by international consensus.[5]

Structure

The human NOV protein contains 357 amino acids with an N-terminal secretory signal peptide followed by four structurally distinct domains with homologies to insulin-like growth factor binding protein (IGFBP), von Willebrand type C repeats (vWC), thrombospondin type 1 repeat (TSR), and a cysteine knot motif within the C-terminal (CT) domain.[6][7]

Function

NOV regulates multiple cellular activities including cell adhesion, migration, proliferation, differentiation, and survival. It functions by direct binding to integrin receptors,[8][9][10] as well as other receptors such as NOTCH1[11] and fibulin 1c (FBLN1).[12] NOV is expressed during wound healing and induces angiogenesis in vivo.[8][10] It is essential for self-renewal of CD34+ hematopoietic stem cells from umbilical cord blood.[13]

NOV can bind BMP2 and inhibit its functions in promoting osteogenic differentiation,[14] and stimulate osteoclastogenesis through a process that may involve calcium flux.[15] Overexpression of Nov in transgenic mice in osteoblasts antagonizes both BMP and Wnt-signaling and result in osteopenia.[16]

In February 2017, it was reported that the NOV protein was involved in regulatory T cell-mediated oligodendrocyte differentiation in the regeneration of myelin following damage to the myelin sheath. This finding revealed a new function for regulatory T cells that is distinct from their role in immunomodulation.[17]

Role in embryo development

In contrast to the lethality of Cyr61 (CCN1) and Ctgf (CCN2) genetic knockout in mice, Nov-null mice are viable and largely normal, exhibiting only modest and transient sexually dimorphic skeletal abnormalities.[18] However, Nov-null mice show enhanced blood vessel neointimal thickening when challenged with vascular injury, indicating that NOV inhibits neoinitimal hyperplasia.[19]

Role in cancer

Although NOV inhibits the proliferation of cancer cells,[20] it appears to promote metastasis.[21][22] Nov overexpression results in reduced tumor size in glioma cells xenografts,[23] but enhances metastatic potential in xenotransplanted melanoma cells.[24] NOV expression is associated with a higher risk of metastasis and worse prognosis in patients with cancers such as Ewing’s sarcoma, melanoma, and breast cancer.[25] In chronic myeloid leukemia (CML), NOV is downregulated as a consequence of the kinase activity of BCR-ABL, a chimeric protein generated through the chromosomal translocation between chromosome 9 and 22.[26] Forced expression of NOV inhibits proliferation and restores growth control in CML cells, suggesting that NOV may be an alternate target for novel therapeutics against CML.[3][27]

References

  1. ↑ Martinerie C, Viegas-Pequignot E, Guenard I, Dutrillaux B, Nguyen VC, Bernheim A, Perbal B (Dec 1992). "Physical mapping of human loci homologous to the chicken nov proto-oncogene". Oncogene. 7 (12): 2529–34. PMID 1334251.
  2. ↑ "Entrez Gene: NOV nephroblastoma overexpressed gene".
  3. ↑ 3.0 3.1 Jun JI, Lau LF (Dec 2011). "Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets". Nature Reviews. Drug Discovery. 10 (12): 945–63. doi:10.1038/nrd3599. PMC 3663145. PMID 22129992.
  4. ↑ Holbourn KP, Acharya KR, Perbal B (Oct 2008). "The CCN family of proteins: structure-function relationships". Trends in Biochemical Sciences. 33 (10): 461–73. doi:10.1016/j.tibs.2008.07.006. PMC 2683937. PMID 18789696.
  5. ↑ Brigstock DR, Goldschmeding R, Katsube KI, Lam SC, Lau LF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M, Yeger H (Apr 2003). "Proposal for a unified CCN nomenclature". Molecular Pathology. 56 (2): 127–8. doi:10.1136/mp.56.2.127. PMC 1187305. PMID 12665631.
  6. ↑ Chen CC, Lau LF (Apr 2009). "Functions and mechanisms of action of CCN matricellular proteins". The International Journal of Biochemistry & Cell Biology. 41 (4): 771–83. doi:10.1016/j.biocel.2008.07.025. PMC 2668982. PMID 18775791.
  7. ↑ Leask A, Abraham DJ (Dec 2006). "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". Journal of Cell Science. 119 (Pt 23): 4803–10. doi:10.1242/jcs.03270. PMID 17130294.
  8. ↑ 8.0 8.1 Lin CG, Leu SJ, Chen N, Tebeau CM, Lin SX, Yeung CY, Lau LF (Jun 2003). "CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family". The Journal of Biological Chemistry. 278 (26): 24200–8. doi:10.1074/jbc.M302028200. PMID 12695522.
  9. ↑ Ellis PD, Metcalfe JC, Hyvönen M, Kemp PR (2003). "Adhesion of endothelial cells to NOV is mediated by the integrins alphavbeta3 and alpha5beta1". Journal of Vascular Research. 40 (3): 234–43. doi:10.1159/000071887. PMID 12902636.
  10. ↑ 10.0 10.1 Lin CG, Chen CC, Leu SJ, Grzeszkiewicz TM, Lau LF (Mar 2005). "Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing". The Journal of Biological Chemistry. 280 (9): 8229–37. doi:10.1074/jbc.M404903200. PMID 15611078.
  11. ↑ Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M, Li CL, Perbal B, Katsube K (Aug 2002). "The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway". The Journal of Biological Chemistry. 277 (33): 29399–405. doi:10.1074/jbc.M203727200. PMID 12050162.
  12. ↑ Perbal B, Martinerie C, Sainson R, Werner M, He B, Roizman B (Feb 1999). "The C-terminal domain of the regulatory protein NOVH is sufficient to promote interaction with fibulin 1C: a clue for a role of NOVH in cell-adhesion signaling". Proceedings of the National Academy of Sciences of the United States of America. 96 (3): 869–74. doi:10.1073/pnas.96.3.869. PMC 15317. PMID 9927660.
  13. ↑ Gupta R, Hong D, Iborra F, Sarno S, Enver T (Apr 2007). "NOV (CCN3) functions as a regulator of human hematopoietic stem or progenitor cells". Science. 316 (5824): 590–3. doi:10.1126/science.1136031. PMID 17463287.
  14. ↑ Minamizato T, Sakamoto K, Liu T, Kokubo H, Katsube K, Perbal B, Nakamura S, Yamaguchi A (Mar 2007). "CCN3/NOV inhibits BMP-2-induced osteoblast differentiation by interacting with BMP and Notch signaling pathways". Biochemical and Biophysical Research Communications. 354 (2): 567–73. doi:10.1016/j.bbrc.2007.01.029. PMID 17250806.
  15. ↑ Ouellet V, Tiedemann K, Mourskaia A, Fong JE, Tran-Thanh D, Amir E, Clemons M, Perbal B, Komarova SV, Siegel PM (May 2011). "CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone". The American Journal of Pathology. 178 (5): 2377–88. doi:10.1016/j.ajpath.2011.01.033. PMC 3081179. PMID 21514448.
  16. ↑ Rydziel S, Stadmeyer L, Zanotti S, Durant D, Smerdel-Ramoya A, Canalis E (Jul 2007). "Nephroblastoma overexpressed (Nov) inhibits osteoblastogenesis and causes osteopenia". The Journal of Biological Chemistry. 282 (27): 19762–72. doi:10.1074/jbc.M700212200. PMID 17500060.
  17. ↑ Dombrowski Y, O'Hagan T, Dittmer M, Penalva R, Mayoral SR, Bankhead P, et al. (May 2017). "Regulatory T cells promote myelin regeneration in the central nervous system". Nature Neuroscience. 20 (5): 674–680. doi:10.1038/nn.4528. PMID 28288125. Lay summary – BBC News.
  18. ↑ Canalis E, Smerdel-Ramoya A, Durant D, Economides AN, Beamer WG, Zanotti S (Jan 2010). "Nephroblastoma overexpressed (Nov) inactivation sensitizes osteoblasts to bone morphogenetic protein-2, but nov is dispensable for skeletal homeostasis". Endocrinology. 151 (1): 221–33. doi:10.1210/en.2009-0574. PMC 2803142. PMID 19934377.
  19. ↑ 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 (Apr 2010). "CCN3 inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration". Arteriosclerosis, Thrombosis, and Vascular Biology. 30 (4): 675–82. doi:10.1161/ATVBAHA.110.203356. PMID 20139355.
  20. ↑ Bleau AM, Planque N, Lazar N, Zambelli D, Ori A, Quan T, Fisher G, Scotlandi K, Perbal B (Aug 2007). "Antiproliferative activity of CCN3: involvement of the C-terminal module and post-translational regulation" (PDF). Journal of Cellular Biochemistry. 101 (6): 1475–91. doi:10.1002/jcb.21262. PMID 17340618.
  21. ↑ Benini S, Perbal B, Zambelli D, Colombo MP, Manara MC, Serra M, Parenza M, Martinez V, Picci P, Scotlandi K (Jun 2005). "In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type". Oncogene. 24 (27): 4349–61. doi:10.1038/sj.onc.1208620. PMID 15824736.
  22. ↑ Perbal B (2006). "The CCN3 protein and cancer". Advances in Experimental Medicine and Biology. 587: 23–40. doi:10.1007/978-1-4020-5133-3_3. PMID 17163153.
  23. ↑ Gupta N, Wang H, McLeod TL, Naus CC, Kyurkchiev S, Advani S, Yu J, Perbal B, Weichselbaum RR (Oct 2001). "Inhibition of glioma cell growth and tumorigenic potential by CCN3 (NOV)". Molecular Pathology. 54 (5): 293–9. doi:10.1136/mp.54.5.293. PMC 1187085. PMID 11577170.
  24. ↑ Vallacchi V, Daniotti M, Ratti F, Di Stasi D, Deho P, De Filippo A, Tragni G, Balsari A, Carbone A, Rivoltini L, Parmiani G, Lazar N, Perbal B, Rodolfo M (Feb 2008). "CCN3/nephroblastoma overexpressed matricellular protein regulates integrin expression, adhesion, and dissemination in melanoma". Cancer Research. 68 (3): 715–23. doi:10.1158/0008-5472.CAN-07-2103. PMID 18245471.
  25. ↑ Perbal B, Lazar N, Zambelli D, Lopez-Guerrero JA, Llombart-Bosch A, Scotlandi K, Picci P (Oct 2009). "Prognostic relevance of CCN3 in Ewing sarcoma". Human Pathology. 40 (10): 1479–86. doi:10.1016/j.humpath.2009.05.008. PMID 19695675.
  26. ↑ McCallum L, Price S, Planque N, Perbal B, Pierce A, Whetton AD, Irvine AE (Sep 2006). "A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation". Blood. 108 (5): 1716–23. doi:10.1182/blood-2006-04-016113. PMID 16670264.
  27. ↑ McCallum L, Lu W, Price S, Lazar N, Perbal B, Irvine AE (Mar 2012). "CCN3 suppresses mitogenic signalling and reinstates growth control mechanisms in Chronic Myeloid Leukaemia". Journal of Cell Communication and Signaling. 6 (1): 27–35. doi:10.1007/s12079-011-0142-2. PMC 3271200. PMID 21773872.
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