NOV (gene) explained

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 is regulated by the hematopoietic transcription factor MZF-1.[14]

NOV can bind BMP2 and inhibit its functions in promoting osteogenic differentiation,[15] and stimulate osteoclastogenesis through a process that may involve calcium flux.[16] Overexpression of Nov in transgenic mice in osteoblasts antagonizes both BMP and Wnt-signaling and result in osteopenia.[17]

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.[18] NOV (CCN3) has recently been implicated in mood disorders, notably in the postpartum period; these effects may be mediated by its effects on myelination [19]

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.[20] However, Nov-null mice show enhanced blood vessel neointimal thickening when challenged with vascular injury, indicating that NOV inhibits neoinitimal hyperplasia.[21]

Role in cancer

Although NOV inhibits the proliferation of cancer cells,[22] it appears to promote metastasis.[23] [24] Nov overexpression results in reduced tumor size in glioma cells xenografts,[25] but enhances metastatic potential in xenotransplanted melanoma cells.[26] 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.[27] 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.[28] 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] [29]

Notes and References

  1. Martinerie C, Viegas-Pequignot E, Guenard I, Dutrillaux B, Nguyen VC, Bernheim A, Perbal B . Physical mapping of human loci homologous to the chicken nov proto-oncogene . Oncogene . 7 . 12 . 2529–34 . Dec 1992 . 1334251 .
  2. Web site: Entrez Gene: NOV nephroblastoma overexpressed gene.
  3. Jun JI, Lau LF . Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets . Nature Reviews. Drug Discovery . 10 . 12 . 945–63 . Dec 2011 . 22129992 . 10.1038/nrd3599 . 3663145 .
  4. Holbourn KP, Acharya KR, Perbal B . The CCN family of proteins: structure-function relationships . Trends in Biochemical Sciences . 33 . 10 . 461–73 . Oct 2008 . 18789696 . 2683937 . 10.1016/j.tibs.2008.07.006 .
  5. Brigstock DR, Goldschmeding R, Katsube KI, Lam SC, Lau LF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M, Yeger H . Proposal for a unified CCN nomenclature . Molecular Pathology . 56 . 2 . 127–8 . Apr 2003 . 12665631 . 1187305 . 10.1136/mp.56.2.127 .
  6. Chen CC, Lau LF . Functions and mechanisms of action of CCN matricellular proteins . The International Journal of Biochemistry & Cell Biology . 41 . 4 . 771–83 . Apr 2009 . 18775791 . 2668982 . 10.1016/j.biocel.2008.07.025 .
  7. Leask A, Abraham DJ . All in the CCN family: essential matricellular signaling modulators emerge from the bunker . Journal of Cell Science . 119 . Pt 23 . 4803–10 . Dec 2006 . 17130294 . 10.1242/jcs.03270 . free .
  8. Lin CG, Leu SJ, Chen N, Tebeau CM, Lin SX, Yeung CY, Lau LF . CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family . The Journal of Biological Chemistry . 278 . 26 . 24200–8 . Jun 2003 . 12695522 . 10.1074/jbc.M302028200 . free .
  9. Ellis PD, Metcalfe JC, Hyvönen M, Kemp PR . Adhesion of endothelial cells to NOV is mediated by the integrins alphavbeta3 and alpha5beta1 . Journal of Vascular Research . 40 . 3 . 234–43 . 2003 . 12902636 . 10.1159/000071887 . 84511515 .
  10. Lin CG, Chen CC, Leu SJ, Grzeszkiewicz TM, Lau LF . Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing . The Journal of Biological Chemistry . 280 . 9 . 8229–37 . Mar 2005 . 15611078 . 10.1074/jbc.M404903200 . free .
  11. Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M, Li CL, Perbal B, Katsube K . 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 . Aug 2002 . 12050162 . 10.1074/jbc.M203727200 . free .
  12. Perbal B, Martinerie C, Sainson R, Werner M, He B, Roizman B . 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 . Feb 1999 . 9927660 . 15317 . 10.1073/pnas.96.3.869 . 1999PNAS...96..869P . free .
  13. 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 . 5824 . 590–3 . Apr 2007 . 17463287 . 10.1126/science.1136031 . 2007Sci...316..590G . 37529465 .
  14. Piszczatowski RT, Rafferty BJ, Rozado A, Parziale JV, Lents NH . Myeloid Zinc Finger 1 (MZF-1) Regulates Expression of the CCN2/CTGF and CCN3/NOV Genes in the Hematopoietic Compartment . Journal of Cellular Physiology . 230 . 11 . 2634–2639 . November 2015 . 25899830 . 10.1002/jcp.25021 . 6888015 . free .
  15. Minamizato T, Sakamoto K, Liu T, Kokubo H, Katsube K, Perbal B, Nakamura S, Yamaguchi A . 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 . Mar 2007 . 17250806 . 10.1016/j.bbrc.2007.01.029 .
  16. Ouellet V, Tiedemann K, Mourskaia A, Fong JE, Tran-Thanh D, Amir E, Clemons M, Perbal B, Komarova SV, Siegel PM . CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone . The American Journal of Pathology . 178 . 5 . 2377–88 . May 2011 . 21514448 . 3081179 . 10.1016/j.ajpath.2011.01.033 .
  17. Rydziel S, Stadmeyer L, Zanotti S, Durant D, Smerdel-Ramoya A, Canalis E . Nephroblastoma overexpressed (Nov) inhibits osteoblastogenesis and causes osteopenia . The Journal of Biological Chemistry . 282 . 27 . 19762–72 . Jul 2007 . 17500060 . 10.1074/jbc.M700212200 . free .
  18. Dombrowski Y, O'Hagan T, Dittmer M, Penalva R, Mayoral SR, Bankhead P, Fleville S, Eleftheriadis G, Zhao C, Naughton M, Hassan R, Moffat J, Falconer J, Boyd A, Hamilton P, Allen IV, Kissenpfennig A, Moynagh PN, Evergren E, Perbal B, Williams AC, Ingram RJ, Chan JR, Franklin RJ, Fitzgerald DC . 6 . Regulatory T cells promote myelin regeneration in the central nervous system . Nature Neuroscience . 20 . 5 . 674–680 . May 2017 . 28288125 . 10.1038/nn.4528 . 5409501 .
  19. Davies W . An analysis of Cellular Communication Network Factor Proteins as candidate mediators of postpartum psychosis risk . Frontiers in Psychiatry . 10 . 876 . Nov 2019 . 31849729 . 10.3389/fpsyt.2019.00876 . 6901936 . free .
  20. Canalis E, Smerdel-Ramoya A, Durant D, Economides AN, Beamer WG, Zanotti S . Nephroblastoma overexpressed (Nov) inactivation sensitizes osteoblasts to bone morphogenetic protein-2, but nov is dispensable for skeletal homeostasis . Endocrinology . 151 . 1 . 221–33 . Jan 2010 . 19934377 . 2803142 . 10.1210/en.2009-0574 .
  21. 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 . Arteriosclerosis, Thrombosis, and Vascular Biology . 30 . 4 . 675–82 . Apr 2010 . 20139355 . 10.1161/ATVBAHA.110.203356 . free .
  22. Bleau AM, Planque N, Lazar N, Zambelli D, Ori A, Quan T, Fisher G, Scotlandi K, Perbal B . Antiproliferative activity of CCN3: involvement of the C-terminal module and post-translational regulation . Journal of Cellular Biochemistry . 101 . 6 . 1475–91 . Aug 2007 . 17340618 . 10.1002/jcb.21262 . 2027.42/56135 . 18256267 . free .
  23. Benini S, Perbal B, Zambelli D, Colombo MP, Manara MC, Serra M, Parenza M, Martinez V, Picci P, Scotlandi K . In Ewing's sarcoma CCN3(NOV) inhibits proliferation while promoting migration and invasion of the same cell type . Oncogene . 24 . 27 . 4349–61 . Jun 2005 . 15824736 . 10.1038/sj.onc.1208620 . free .
  24. Book: Perbal B . New trends in cancer for the 21st century . The CCN3 Protein and Cancer . Advances in Experimental Medicine and Biology . 587 . 23–40 . 2006 . 17163153 . 10.1007/978-1-4020-5133-3_3. 978-1-4020-4966-8 .
  25. Gupta N, Wang H, McLeod TL, Naus CC, Kyurkchiev S, Advani S, Yu J, Perbal B, Weichselbaum RR . Inhibition of glioma cell growth and tumorigenic potential by CCN3 (NOV) . Molecular Pathology . 54 . 5 . 293–9 . Oct 2001 . 11577170 . 1187085 . 10.1136/mp.54.5.293 .
  26. 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 . CCN3/nephroblastoma overexpressed matricellular protein regulates integrin expression, adhesion, and dissemination in melanoma . Cancer Research . 68 . 3 . 715–23 . Feb 2008 . 18245471 . 10.1158/0008-5472.CAN-07-2103 . free .
  27. Perbal B, Lazar N, Zambelli D, Lopez-Guerrero JA, Llombart-Bosch A, Scotlandi K, Picci P . Prognostic relevance of CCN3 in Ewing sarcoma . Human Pathology . 40 . 10 . 1479–86 . Oct 2009 . 19695675 . 10.1016/j.humpath.2009.05.008 .
  28. McCallum L, Price S, Planque N, Perbal B, Pierce A, Whetton AD, Irvine AE . A novel mechanism for BCR-ABL action: stimulated secretion of CCN3 is involved in growth and differentiation regulation . Blood . 108 . 5 . 1716–23 . Sep 2006 . 16670264 . 10.1182/blood-2006-04-016113 . free .
  29. McCallum L, Lu W, Price S, Lazar N, Perbal B, Irvine AE . CCN3 suppresses mitogenic signalling and reinstates growth control mechanisms in Chronic Myeloid Leukaemia . Journal of Cell Communication and Signaling . 6 . 1 . 27–35 . Mar 2012 . 21773872 . 3271200 . 10.1007/s12079-011-0142-2 .

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