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And the CCN Family of Genes: Structural and Functional Issues J Clin Pathol: Mol Pathol 2001;54:57–79 57 Review Mol Path: first published as 10.1136/mp.54.2.57 on 1 April 2001. Downloaded from NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues B Perbal Abstract terminus is expected to confer on the The CCN family of genes presently con- truncated polypeptide constitutive posi- sists of six distinct members encoding tive or negative activities. proteins that participate in fundamental (J Clin Pathol: Mol Pathol 2001;54:57–79) biological processes such as cell prolifera- tion, attachment, migration, diVerentia- Keywords: cancer; diVerentiation; signalling; develop- tion, wound healing, angiogenesis, and ment; angiogenesis; fibrosis; ctgf; cyr61; wisp; CCN several pathologies including fibrosis and tumorigenesis. Whereas CYR61 and CTGF were reported to act as positive The regulation of cellular growth, diVerentia- regulators of cell growth, NOV (nephrob- tion, and death is central to a myriad of lastoma overexpressed) provided the first biological processes that govern the appear- example of a CCN protein with negative ance, maintenance, and termination of life. regulatory properties and the first exam- Although many genes whose products are ple of aberrant expression being associ- reported to play a key role in cell growth con- ated with tumour development. The trol have been described, several basic regula- subsequent discovery of the ELM1, tory circuits involve proteins yet to be identi- rCOP1, and WISP proteins has broadened fied. http://mp.bmj.com/ The discovery of three structurally related the variety of functions attributed to the genes whose expression was modulated by CCN proteins and has extended previous growth factors and altered in cancer cells has observations to other biological systems. led to the recognition of a new family of cell This review discusses fundamental ques- growth regulators with unique biological prop- tions regarding the regulation of CCN erties. gene expression in normal and pathologi- Bork1 first proposed that these genes should on September 29, 2021 by guest. Protected copyright. cal conditions, and the structural basis for be designated the CCN family of genes, which their specific biological activity. After dis- stands for Cyr61 (cystein rich protein), Ctgf cussing the role of nov and other CCN (connective tissue growth factor), and Nov proteins in the development of a variety of (nephroblastoma overexpressed gene). The diVerent tissues such as kidney, nervous existence of this family of genes has recently system, muscle, cartilage, and bone, the been reinforced by the discovery of three new altered expression of the CCN proteins in members (see below). various pathologies is discussed, with an For many years, the CCN proteins seemed emphasis on the altered expression of nov not to share much more than their strikingly in many diVerent tumour types such as conserved primary structure and no physi- Wilms’s tumour, renal cell carcinomas, ological or biological properties had been prostate carcinomas, osteosarcomas, clearly assigned to them. chondrosarcomas, adrenocortical carci- The bulk of the recent results presented at nomas, and neuroblastomas. The possible the first international workshop on the CCN Laboratoire d’ use of nov as a tool for molecular medicine family of genes and the increasing pace at Oncologie Virale et is also discussed. The variety of biological Moléculaire, UFR de which papers are being published in this field Biochimie, Université functions attributed to the CCN proteins point to the increased attention being focused Paris 7-D. Diderot, 2 has led to the proposal of a model in which on these proteins. Their roles are being clearly Place Jussieu, 75 005 physical interactions between the amino established in fundamental biological proc- Paris, France and carboxy portions of the CCN proteins esses such as cell proliferation, attachment, B Perbal modulate their biological activity and migration, and diVerentiation, wound healing, Correspondence to: ensure a proper balance of positive and angiogenesis, and several pathologies including Professor Perbal negative signals through interactions with fibrosis and tumorigenesis. Furthermore, it [email protected] other partners. In this model, disruption appears that in spite of their highly conserved Accepted for publication of the secondary structure of the CCN structure, these proteins display non- 9 January 2001 proteins induced by deletions of either redundant functions, which are apparently www.molpath.com 58 Perbal cyr61 Cystein rich 61 CEF10 (chicken embryo fibroblasts) (Ck) nuclear run on transcription assays. This (1p22.3) βIG1 (TGFβ induced gene) cyr61 (Mu) aspect must be approached with extreme cau- tion because it has a pronounced impact on Mol Path: first published as 10.1136/mp.54.2.57 on 1 April 2001. Downloaded from ctgf Connective tissue Ctgf (Ck) ctgf (Sw) ctgf (Xn) our way of thinking when analysing the (6q23.1) growth factor bIG2 (TGFβ induced gene) (Mu) biological properties of potential regulatory Fisp 12 (fibroblast inducible secreted protein) (Mu) molecules, such as CCN proteins, whose nov Nephroblastoma nov (Ck) novM (Mu) nov (Sw) nov (Xn) (8q24.1) overexpressed expression is developmentally regulated in a spatiotemporal way. WISP-1 Wnt-1 induced Elm1 (expressed in low metastatic type 1 cells) (Mu) (8q24.1–24.3) secreted protein Wisp 1 (Mu) GENES THAT WERE ISOLATED ON THE BASIS OF THEIR DIFFERENTIAL EXPRESSION IN QUIESCENT WISP-2 Wnt-1 induced rCop-1 (expression lost after transformation) (Mu) AND SERUM STIMULATED CELLS (20q12–13) secreted protein HICP (heparin induced CCN-like protein) Under starvation conditions (incubation in low Wisp 2 (Mu) serum concentration), confluent cells stop WISP-3 Wnt-1 induced growing and reach the G0 state of the cell (6q23.1) secreted protein cycle. G1 phase re-entry of the starved cells Figure 1 The CCN family of genes. The names and chromosomal localisations of the upon treatment with serum triggers the stimu- human CCN genes are indicated in the left column. lation of immediate early genes, whose expres- required at diVerent locations and at diVerent sion proceeds shortly after serum stimulation, times along the same biological pathways. without the need for de novo protein synthesis Understanding the structural and functional (the immediate early terminology was used by bases for the molecular diversity of the CCN comparison with the ordered expression of family is an important challenge. It will set the viral genes upon infection of eukaryotic cells). stage for understanding the role of these genes Characterisation of these immediate genes in the control of cellular proliferation, diVeren- provided important clues as to the type of tiation, and death, thereby allowing the use of genes responsible for the regulation of master these genes and proteins in modern biomedi- switches involved in the control of cell growth. cal technologies for early diagnosis and This experimental approach, which had pre- treatment. viously led to the discovery of a variety of Because recent publications have dealt in signalling proteins and transcription factors, detail with the description of the CCN genes led to the isolation of the murine cyr61 and and corresponding proteins,2–4 this review will fisp12 genes. deal with some fundamental questions regard- Fibroblastic cells of diVerent origins have ing the expression of CCN proteins in normal been used to analyse gene expression during and pathological conditions, and the structural serum induced G0/G1 transition. DiVerential basis for their specific biological activity, with screening of a cDNA library prepared from an emphasis on studies performed on the nov serum stimulated mouse BALB/c3T3 fibro- http://mp.bmj.com/ gene in my laboratory. blasts led to the isolation of cyr61, which encodes a secreted 379 residue polypeptide of Isolation of the CCN genes apparent molecular mass 42 kDa,5 whereas a The CCN family of genes presently consists of similar strategy performed with mouse six distinct members in the human (fig 1), the NIH3T3 cells led to the isolation of fisp12, orthologues of which have been described in which encodes a secreted 348 residue polypep- several diVerent species ranging from xenopus tide of 37 kDa.6 The early expression of these on September 29, 2021 by guest. Protected copyright. to rodents. genes in the cell cycle without the need of prior The way in which the CCN genes were iso- protein synthesis categorised them as immedi- lated might provide valuable information for ate early genes. understanding their diVerential expression and Early studies established that immediate biological properties. The diVerent strategies early genes were expressed transiently and were that have led to the isolation of CCN genes either required for the G0–G1 transition or for include: subtractive hybridisation and diVeren- G1 progression to S phase. In the first group, tial display of RNAs whose expression is c-fos expression is induced between 20 and 90 aVected in normal cells stimulated to grow by minutes and decreases to undetectable levels serum, growth factors, and viruses, or in after two hours, whereas in the second group, tumour cells as compared with their normal c-myc expression is induced between 45 counterparts. minutes and three hours and is detectable up to The diVerential screening strategies are six hours after serum stimulation. based on the fact that RNA species are under Both cyr61 and fisp12 showed the same represented or lacking in one of the two situa- rapid induction pattern, starting 30 minutes tions analysed. Although most authors at- after serum stimulation and peaking between tribute increased RNA values to stimulation of one and two hours after stimulation. In both transcription, it is important to keep in mind cases, short half life (30 minutes for cyr61, that RNA metabolism can be aVected dra- 10–15 minutes for fisp12) RNA species were matically by the events that lead to transfor- produced, and sustained expression was ob- mation or induction of proliferation in re- served over several hours after the addition of sponse to viral infection and growth factors.
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