NOV (gene)

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Nephroblastoma overexpressed
Identifiers
Symbols NOV ; CCN3; IBP-9; IGFBP-9; IGFBP9; NOVh
External IDs OMIM164958 MGI109185 HomoloGene1884 GeneCards: NOV Gene
RNA expression pattern
PBB GE NOV 214321 at tn.png
PBB GE NOV 204501 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4856 18133
Ensembl ENSG00000136999 ENSMUSG00000037362
UniProt P48745 Q64299
RefSeq (mRNA) NM_002514 NM_010930
RefSeq (protein) NP_002505 NP_035060
Location (UCSC) Chr 8:
120.43 – 120.44 Mb
Chr 15:
54.75 – 54.75 Mb
PubMed search [1] [2]

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

CCN family[edit]

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[edit]

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[edit]

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]

Role in embryo development[edit]

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.[17] However, Nov-null mice show enhanced blood vessel neointimal thickening when challenged with vascular injury, indicating that NOV inhibits neoinitimal hyperplasia.[18]

Role in cancer[edit]

Although NOV inhibits the proliferation of cancer cells,[19] it appears to promote metastasis.[20][21] Nov overexpression results in reduced tumor size in glioma cells xenografts,[22] but enhances metastatic potential in xenotransplanted melanoma cells.[23] 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.[24] 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.[25] 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][26]

References[edit]

  1. ^ Martinerie C, Viegas-Pequignot E, Guenard I, Dutrillaux B, Nguyen VC, Bernheim A, Perbal B (Jan 1993). "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. ^ a b Jun JI, Lau LF (December 2011). "Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets". Nat Rev Drug Discov 10 (12): 945–63. doi:10.1038/nrd3599. PMID 22129992. 
  4. ^ Holbourn KP, Acharya KR, Perbal B (October 2008). "The CCN family of proteins: structure-function relationships". Trends Biochem. Sci. 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 (April 2003). "Proposal for a unified CCN nomenclature". MP, Mol. Pathol. 56 (2): 127–8. doi:10.1136/mp.56.2.127. PMC 1187305. PMID 12665631. 
  6. ^ Chen CC, Lau LF (April 2009). "Functions and mechanisms of action of CCN matricellular proteins". Int. J. Biochem. Cell Biol. 41 (4): 771–83. doi:10.1016/j.biocel.2008.07.025. PMC 2668982. PMID 18775791. 
  7. ^ Leask A, Abraham DJ (December 2006). "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". J. Cell. Sci. 119 (Pt 23): 4803–10. doi:10.1242/jcs.03270. PMID 17130294. 
  8. ^ a b Lin CG, Leu SJ, Chen N, Tebeau CM, Lin SX, Yeung CY, Lau LF (June 2003). "CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family". J. Biol. Chem. 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". J. Vasc. Res. 40 (3): 234–43. doi:10.1159/000071887. PMID 12902636. 
  10. ^ a b Lin CG, Chen CC, Leu SJ, Grzeszkiewicz TM, Lau LF (March 2005). "Integrin-dependent functions of the angiogenic inducer NOV (CCN3): implication in wound healing". J. Biol. Chem. 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 (August 2002). "The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway". J. Biol. Chem. 277 (33): 29399–405. doi:10.1074/jbc.M203727200. PMID 12050162. 
  12. ^ Perbal B, Martinerie C, Sainson R, Werner M, He B, Roizman B (February 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". Proc. Natl. Acad. Sci. U.S.A. 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 (April 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 (March 2007). "CCN3/NOV inhibits BMP-2-induced osteoblast differentiation by interacting with BMP and Notch signaling pathways". Biochem. Biophys. Res. Commun. 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". Am. J. Pathol. 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 (July 2007). "Nephroblastoma overexpressed (Nov) inhibits osteoblastogenesis and causes osteopenia". J. Biol. Chem. 282 (27): 19762–72. doi:10.1074/jbc.M700212200. PMID 17500060. 
  17. ^ Canalis E, Smerdel-Ramoya A, Durant D, Economides AN, Beamer WG, Zanotti S (January 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. 
  18. ^ 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 (April 2010). "CCN3 inhibits neointimal hyperplasia through modulation of smooth muscle cell growth and migration". Arterioscler. Thromb. Vasc. Biol. 30 (4): 675–82. doi:10.1161/ATVBAHA.110.203356. PMID 20139355. 
  19. ^ Bleau AM, Planque N, Lazar N, Zambelli D, Ori A, Quan T, Fisher G, Scotlandi K, Perbal B (August 2007). "Antiproliferative activity of CCN3: involvement of the C-terminal module and post-translational regulation". J. Cell. Biochem. 101 (6): 1475–91. doi:10.1002/jcb.21262. PMID 17340618. 
  20. ^ Benini S, Perbal B, Zambelli D, Colombo MP, Manara MC, Serra M, Parenza M, Martinez V, Picci P, Scotlandi K (June 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. 
  21. ^ Perbal B (2006). "The CCN3 protein and cancer". Adv. Exp. Med. Biol. 587: 23–40. PMID 17163153. 
  22. ^ Gupta N, Wang H, McLeod TL, Naus CC, Kyurkchiev S, Advani S, Yu J, Perbal B, Weichselbaum RR (October 2001). "Inhibition of glioma cell growth and tumorigenic potential by CCN3 (NOV)". MP, Mol. Pathol. 54 (5): 293–9. PMC 1187085. PMID 11577170. 
  23. ^ 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 (February 2008). "CCN3/nephroblastoma overexpressed matricellular protein regulates integrin expression, adhesion, and dissemination in melanoma". Cancer Res. 68 (3): 715–23. doi:10.1158/0008-5472.CAN-07-2103. PMID 18245471. 
  24. ^ Perbal B, Lazar N, Zambelli D, Lopez-Guerrero JA, Llombart-Bosch A, Scotlandi K, Picci P (October 2009). "Prognostic relevance of CCN3 in Ewing sarcoma". Hum. Pathol. 40 (10): 1479–86. doi:10.1016/j.humpath.2009.05.008. PMID 19695675. 
  25. ^ McCallum L, Price S, Planque N, Perbal B, Pierce A, Whetton AD, Irvine AE (September 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. 
  26. ^ McCallum L, Lu W, Price S, Lazar N, Perbal B, Irvine AE (March 2012). "CCN3 suppresses mitogenic signalling and reinstates growth control mechanisms in Chronic Myeloid Leukaemia". J Cell Commun Signal 6 (1): 27–35. doi:10.1007/s12079-011-0142-2. PMC 3271200. PMID 21773872.