Nuclear addressing provides a clue for the transforming activity of amino‐truncated CCN3 proteins

Planque, Nathalie; Li, Chang Long; Saule, Simon; Bleau, Anne-Marie; Perbal, Bernard

doi:10.1002/jcb.20887

Cited by 60 publications

(84 citation statements)

References 37 publications

(61 reference statements)

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“…Although we did not study the short form at the functional level, its nuclear localization in melanoma cells (Fig. 3A and C) is consistent with other studies and with its regulatory effect on transcription (29). Our results do, however, clearly show that the CCN3 fulllength protein is associated with high adhesiveness of melanoma cells to ECM proteins.…”

Section: Discussionsupporting

confidence: 89%

CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma

Vallacchi¹,

Daniotti²,

Ratti³

et al. 2008

Cancer Research

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CCN3/nephroblastoma overexpressed belongs to the CCN family of genes that encode secreted proteins associated with the extracellular matrix (ECM) and exert regulatory effects at the cellular level. Overexpression of CCN3 was shown in metastatic melanoma cells compared with cells of the primary tumor from the same patient. Analysis of short-term cultures from 50 primary and metastatic melanomas revealed a heterogeneous expression pattern of both the 46-kDa fulllength cytoplasmic/secreted protein and the 32-kDa nucleartruncated form. The different protein expression patterns were not associated with gene alterations or polymorphisms. Like the metastatic cells expressing high levels of the 46-kDa CCN3, cells transfected to overexpress CCN3 showed increased adhesion to ECM proteins, whereas inhibition of CCN3 expression by small interfering RNA decreased adhesion to laminin and vitronectin. CCN3 overexpression induced increased expression of laminin and vitronectin integrin receptors A7B1 and AvB5 by increasing their mRNA production. Moreover, CCN3 secreted by melanoma cells acted as an adhesion matrix protein for melanoma cells themselves. Analysis of CCN3 protein expression with respect to melanoma progression detected the protein in all visceral metastases tested and in most nodal metastases from relapsing patients but in only a few nodal metastases from nonrelapsing patients and cutaneous metastases. Consistently, xenotransplantation in immunodeficient mice showed a higher metastatic potential of melanoma cells overexpressing CCN3. Together, these data indicate a role for CCN3 in melanoma cell interaction with the ECM by regulating integrin expression, resulting in altered cell adhesion and leading melanoma progression to aggressive disease. [Cancer Res 2008;68(3):715-23]

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Section: Discussionsupporting

confidence: 89%

CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma

Vallacchi¹,

Daniotti²,

Ratti³

et al. 2008

Cancer Research

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“…Additionally, we may speculate that CCN3 may be directly inhibiting the transcription of CCN2 and CCN4 genes. It is reported that CCN3 is present in the nucleus and behaves like a transcription factor therein (Planque et al 2006). Of our interest, CCN5, another CCN family member, actually regulates gene expression in the nucleus (Sabbah et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Anti-fibrotic effect of CCN3 accompanied by altered gene expression profile of the CCN family

Kader

Kubota

Janune

et al. 2012

J. Cell Commun. Signal.

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CCN family proteins 2 and 3 (CCN2 and CCN3) belong to the CCN family of proteins, all having a high level of structural similarity. It is widely known that CCN2 is a profibrotic molecule that mediates the development of fibrotic disorders in many different tissues and organs. In contrast, CCN3 has been recently suggested to act as an anti-fibrotic factor in several tissues. This CCN3 action was shown earlier to be exerted by the repression of the CCN2 gene expression in kidney tissue, whereas different findings were obtained for liver cells. Thus, the molecular action of CCN3 yielding its anti-fibrotic effect is still controversial. Here, using a general model of fibrosis, we evaluated the effect of CCN3 overexpression on the gene expression of all of the CCN family members, as well as on that of fibrotic marker genes. As a result, repression of CCN2 gene expression was modest, while type I collagen and α-smooth muscle actin gene expression was prominently repressed. Interestingly, not only CCN2, but also CCN4 gene expression showed a decrease upon CCN3 overexpression. These findings indicate that fibrotic gene induction is under the control of a complex molecular network conducted by CCN family members functioning together.

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“…These four domains have been shown to be discrete structural entities and can be produced as individual truncates that still possess biological activity (24). The CCN family is highly conserved at the primary structure level with ϳ30 -50% amino acid identity (and 40 -60% similarity) (28,29). CCN5 is an exception in that it lacks the CT domain but still maintains the first three highly conserved domains, and CCN6 lacks four normally conserved cysteine residues in the VWC domain.…”

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confidence: 99%

First Structural Glimpse of CCN3 and CCN5 Multifunctional Signaling Regulators Elucidated by Small Angle X-ray Scattering

Holbourn

Malfois

Acharya

2011

Journal of Biological Chemistry

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The CCN (cyr61, ctgf, nov) proteins (CCN1-6) are an important family of matricellular regulatory factors involved in internal and external cell signaling. They are central to essential biological processes such as adhesion, proliferation, angiogenesis, tumorigenesis, wound healing, and modulation of the extracellular matrix. They possess a highly conserved modular structure with four distinct modules that interact with a wide range of regulatory proteins and ligands. However, at the structural level, little is known although their biological function(s) seems to require cooperation between individual modules. Here we present for the first time structural determinants of two of the CCN family members, CCN3 and CCN5 (expressed in Escherichia coli), using small angle x-ray scattering. The results provide a description of the overall molecular shape and possible general three-dimensional modular arrangement for CCN proteins. These data unequivocally provide insight of the nature of CCN protein(s) in solution and thus important insight into their structure-function relationships.

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Nuclear addressing provides a clue for the transforming activity of amino‐truncated CCN3 proteins

Cited by 60 publications

References 37 publications

CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma

CCN3/Nephroblastoma Overexpressed Matricellular Protein Regulates Integrin Expression, Adhesion, and Dissemination in Melanoma

Anti-fibrotic effect of CCN3 accompanied by altered gene expression profile of the CCN family

First Structural Glimpse of CCN3 and CCN5 Multifunctional Signaling Regulators Elucidated by Small Angle X-ray Scattering

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