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Report on the 8Th International Workshop on the CCN Family of Genes – Nice November 3–8, 2015

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Report on the 8Th International Workshop on the CCN Family of Genes – Nice November 3–8, 2015 J. Cell Commun. Signal. (2016) 10:77–86 DOI 10.1007/s12079-016-0317-y EDITORIAL Report on the 8th international workshop on the CCN family of genes – Nice November 3–8, 2015 Bernard Perbal1 & Lester Lau 2 & Karen Lyons3 & Satoshi Kubota4 & Herman Yeger5 & Gary Fisher6 Received: 29 January 2016 /Accepted: 29 January 2016 /Published online: 26 February 2016 # The International CCN Society 2016 The 8th international workshop on the CCN family of genes was able and enthusiastic about participating with us in the full was held for a second time in Nice, from November 3rd to 8th, sessions of the meeting. It is always a unique and fruitful 2015. Under particularly sunny and warm weather everyone opportunity for all participants, either young or established enjoyed the charms of the Mediterranean coastline. scientists, to share time with the awardees. Thanks to Annick Perbal, the social events during the meet- This year we also had the pleasure to welcome Robert ing were a real success and were truly well appreciated by all. Baxter, a former ICCNS-Springer awardee, who flew in from The choice of the Westminster hotel was an excellent one. Australia to join us and present a special conference on the role of This year the ICCNS honored and warmly welcomed IGFBP3 in the breast cancer response to DNA damaging Judith Campisi, the recipient of the 2015 ICCNS-Springer therapy. award, who accepted to present a conference on senescence Those who did not have the opportunity to make it at the time and cancer. We are grateful to Judith Campisi who came a Robert Baxter received the award in Sydney, could then enjoy long way from San Francisco, despite being under the weather sharing experiences and discuss possible levels of interactions with a bad cold and sore throat. We also appreciate that she between the ICCNS and IGF societies. All attendees agreed that the quality of the science present- ed at the meeting was excellent. All speakers made the effort * Bernard Perbal to include in their presentation a concise overview of their [email protected] topic, which made their talk appreciable to all, including new- comers to the CCN field. Several participants who were attending the meeting for the 1 Sources et Méthodologie du Droit Economique, first time informed us, to our great satisfaction, that they GREDEG-CREDECO CNRS UMR 7321 Université de would make sure to come back for the 9th edition ! Nice-Sophia Antipolis and International CCN Society, Nice, France In his scientific introduction to the meeting, Bernard 2 Department of Biochemistry and Molecular Genetics, University of Perbal addressed questions regarding the progress made over Illinois at Chicago, Chicago, IL 60607, USA the past decade in the understanding of the variety and com- 3 Department of Molecular, Cell & Developmental Biology, plexity of functions assigned to the CCN proteins. Department of Orthopaedic Surgery, University of California Los The bulk of data obtained over a few years period following Angeles, Los Angeles, CA, USA 4 the discovery of the three founding members of the CCN family Department of Biochemistry and Molecular Dentistry, Dentistry and [(CCN1/cyr61; CCN2/ctgf and CCN3/nov), and the Wnt- Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan induced secreted proteins that were later identified as CCN pro- teins (CCN4-6)], set the stage for a new scientific era that proved 5 Program in Developmental & Stem Cell Biology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, rich in exciting discoveries on CCN proteins with promise for Toronto, ON, Canada contributing to the betterment of human welfare. 6 Department of Dermatology, University of Michigan, Ann Results obtained in the early 90s established the bipartite Arbor, MI, USA functionality of the CCN family of proteins, with different 78 B. Perbal et al. members involved in either the stimulation or in the inhibition In this model, the bioavailability of each ligand and partner of cell proliferation. that interact with the various CCN modules dictates potential- From one point of view past observations, can be considered ly the activation or inhibition of regulatory signaling path- either negatively as what has been wiped off by the action of ways.Tissuespecificexpression of ligands, partners and time, or positively as the bulk of what remains and on which CCN proteins coupled to their temporal regulation of expres- future efforts are to be built. New « pioneers » cannot just wipe sion provides the basis for a complex network of combinato- out the past and then present models that are in fact based on rial events, the existence of which being critical to the cou- previously published concepts. As stated by B. Perbal, it is quite pling and coordination of different regulatory pathways in disturbing that the bibliographic citations of many newly which CCN proteins are known to participate. published manuscripts do not extend more than a decade ago, Deciphering novel aspects of CCN proteins expression and at the most. In effect, the field needs to move forward and avoid functions was the topic of session I. George Bou-Gharios re- conceptual stalling. ported the identification of new enhancer sequences that are in- That the CCN proteins act in concert, either as agonists or volved in the control of CCN2 tissue-specific expression. antagonists has been established since the early 90s. What Takashi Nishida presented data supporting the idea that activa- remains to be understood are the molecular bases for their tion of RhoA and MAPK signaling induced by low intensity opposite or synergistic actions, and non-redundant functions. pulsed ultrasound (LIPUS)-stimulated Ca2+ influx resulted in B. Perbal also stressed that surprisingly, very little information an increased CCN2 production which in turn induced chondro- has stemmed from a structure-function analysis of the various cyte differentiation, and Koichiro Muromachi reported data CCN proteins. There is no doubt that the field suffers from the showing regulation of CCN2 expression and membrane glyco- lack of information regarding the functional specificity of the sylation in the human dental pulp, by the bone morphogenetic four constitutive modules that make up the biologically active protein BMP-1. A new role for CCN2 in maintaining both ener- CCN proteins. gy supply and balanced aminoacid metabolism in chondrocytes Swapping of the four protein domains as was performed in the was discussed in the presentation given by Satoshi Kubota. case of IGFBP3 and CCN3, would certainly help to better un- Stimulation of osteoblast and osteoclast differentiation by derstand a fascinating paradox and pinpoint the essential compo- lysyl oxidase propeptides, with a possible role for CCN2 was nents that are responsible for the highly specific functions of presented by Philip Trackman, whereas data presented by CCN proteins that share a high degree of structural conservation. Mitsushiro Hoshijima suggested novel functions of a For example, introducing the CT module of a CCN pro- CCN2-rab14 association in proteoglycan synthesis by teins that belong to either the positive or negative group of chondrocytes. regulators, into CCN5 which is deprived of a CT module, The regulation of gene expression is known to involve a would certainly allow one to grasp some of the functions of whole series of specific DNA sequences and structural mod- this domain in different structural contexts. ifications of histones, as established by the identification of Likewise, directed mutagenesis of cysteine in CCN pro- DNAse hypersensitive regions in the vicinity of coding teins is expected to be informative, since it is widely accepted, sequences. without any kind of experimental demonstration, that the Historically, proximal elements were first identified up- pairwise association of the 38 conserved cysteine residues in stream of the core promoter sequences at which initiation of CCN proteins is responsible for the function of each domain. transcription by RNA polymerase begins. However, a close examination of predicted secondary Histone modifications associated with the regulation of structures reveals that in spite of the high degree of conserva- gene transcription were identified as part of downstream, up- tion of cysteine residues, both in place and number, in the stream and distal regulatory elements. different CCN proteins, the presence of these residues in As nicely reviewed by G. Bou Gharios, the tissue specific slightly different primary structure environments, does not regulation of CCN2 expression involves several regulatory ele- appear to impact the secondary structure in a similar way. ments localized upstream and downstream of the coding Understanding these spatial interactions is critical to a better sequences. knowledge of the structural bases for CCN biological functions. Early work from Grotendorst’s group identified TGF beta On another standpoint, and in the light of new recent results, response elements in the −134–169 region upstream to the B. Perbal came back to a model that he proposed in 2001 that CCN2 transcription start in addition to several other canonical might account for the striking functional diversity of the CCN regulatory sites. Additional data obtained by other groups proteins. This model is based on the observations that i) the established that regulation of CCN2 gene transcription by TGF expression of the CCN proteins is subject to a tight spatial and beta is SMAD-dependent. Induction of CCN2 by TGF beta in temporal regulation, and ii) each domain of the CCN proteins has fibroblasts requires both SMADs and TGF beta elements. been reported to interact physically with several key components A set of DNA sequences localized between −202 and −180 of cellular regulatory pathways. upstream of the CCN2 transcription start site was later found Report on the 8th international workshop on the CCN family of genes 79 to function as a dominant transcription enhancer in Muromachi et al. aimed to clarify the relative involvement chondrocytes.
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