Regulation of the CCN genes by vitamin D: A possible adjuvant therapy in the treatment of cancer and fibrosis

Piszczatowski, Richard T.; Lents, Nathan H.

doi:10.1016/j.cellsig.2016.07.009

Cited by 6 publications

(6 citation statements)

References 123 publications

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“…It is therefore both intriguing and relevant that Vitamin D may play an important role in the regulation of CCN genes with implications for general health and in pathological conditions such as fibrosis and cancer (reviewed in Piszczatowski and Lents 2016). We predict that continuing research on the CCN family of proteins will shed a bright light on their biological roles.…”

Section: Summary and Perspectivementioning

confidence: 99%

CCN family of proteins: critical modulators of the tumor cell microenvironment

Yeger

Perbal

2016

J. Cell Commun. Signal.

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The CCN family of proteins consisting of CCN1 (Cyr61), CCN2 (CTGF), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3) are considered matricellular proteins operating essentially in the extracellular microenvironment between cells. Evidence has also been gradually building since their first discovery of additional intracellular roles although the major activity is triggered at the cell membrane. The proteins consist of 4 motifs, a signal peptide (for secretion} followed consecutively by the IGFBP, VWC, TSP1 and CT (C-terminal cysteine knot domain) motifs, which signify their potential binding partners and functional connections to a variety of key regulators of physiological processes. With respect to cancer it is now clear that, whereas certain members can facilitate tumor behavior and progression, others can competitively counter the process. It is therefore clear that the net outcome of biological interactions in the matrix and what gets signaled or inhibited can be a function of the interplay of these CCN 1-6 proteins. Because the CCN proteins further interact with other key proteins, like growth factors in the matrix, the balance is not only important but can vary dynamically with the physiological states of tumor cells and the surrounding normal cells. The tumor niche with its many cell players has surfaced as a critical determinant of tumor behavior, invasiveness, and metastasis. It is in this context that CCN proteins should be investigated with the potential of being recognized and validated for future therapeutic approaches.

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Section: Summary and Perspectivementioning

confidence: 99%

CCN family of proteins: critical modulators of the tumor cell microenvironment

Yeger

Perbal

2016

J. Cell Commun. Signal.

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“…The fibrils account for one-third of the mass of vertebrates 3 and are sites of attachment for a wide range of macromolecules including integrins, making them essential for metazoan development 4,5 . The importance of tight cellular control of collagen fibril homeostasis is exemplified in fibrosis, which is characterized by accumulation of collagen fibrils and is a feature of 45% of all deaths 6 including those caused by cancer 7 , and in musculoskeletal disease in which loss of collagen leads to tissue frailty. A remarkable feature of collagen fibrils is that they are formed during embryogenesis 8 and remain without turnover for the life of the animal as evidenced by studies showing that the half-life of collagen in tendon and cartilage exceeds 200 years [9][10][11][12][13] .…”

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confidence: 99%

Circadian control of the secretory pathway is a central mechanism in tissue homeostasis

Chang

Garva

Pickard

et al. 2018

Preprint

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Collagen is the most abundant secreted protein in vertebrates that persists throughout life without renewal. The unchanging nature of collagen contrasts with observed continued collagen synthesis throughout adulthood and with conventional transcriptional and translational homeostatic mechanisms that replace damaged proteins with new copies. Here we show circadian clock regulation of procollagen transport from ER-to-Golgi and Golgi-to-plasma membrane by sequential rhythmic expression of SEC61, TANGO1, PDE4D and VPS33B. The result is nocturnal procollagen synthesis and daytime collagen fibril assembly in mice. Rhythmic collagen degradation by CTSK maintains collagen homeostasis. This circadian cycle of collagen synthesis, assembly and degradation affects only a pool of newly-synthesized collagen whilst maintaining the persistent collagen network. Disabling the circadian clock causes collagen accumulation and abnormal fibrils in vivo. In conclusion, our study has identified a circadian clock mechanism of protein homeostasis in which a sacrificial pool of collagen is synthesized and removed to maintain tissue function.

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“…As previously reported, some CCN proteins activates its profibrotic signaling by binding some receptors, such as HSPGs, tyrosine kinase receptor (TrkA), epidermal growth factor receptor (EGFR), and LRP. In addition, CCN proteins could directly interact with cell surface integrins, growth factors, cytokines, matrix metalloproteinases (MMPs), and other ECM proteins (Figure 1; Holbourn et al, 2008; Leask & Abraham, 2006; Piszczatowski & Lents, 2016). Due to their frequent interaction with signaling components of the ECM, CCN proteins are known to be highly implicated in various biological processes including angiogenesis, adhesion, ECM remodeling, skeletal development, and wound repair, as well as affecting proliferation and migration of distinct cell types (Chen & Brigstock, 2017; Holbourn et al, 2008; Murphy‐Marshman et al, 2017; Piszczatowski & Lents, 2016).…”

Section: Ccn Receptors and Signaling Pathwaysmentioning

confidence: 99%

Emerging role of CCN family proteins in fibrosis

Sun

Zhang

Liu

2020

Journal Cellular Physiology

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Fibrosis is a common pathological change characterized by the excessive accumulation of fibrous connective tissue. Once uncontrolled, this pathological progress can lead to irreversible damage to the structure and function of organs, which is a serious threat to human health and life. Actually, the disability and death of patients caused by many chronic diseases have a closed relationship with fibrosis. The CCN protein family, including six members, is a small group of matrix proteins exhibiting structurally similar features. In the past 20 years, different biological functions of CCN proteins have been identified in various diseases. Of note, it has been recently shown that they are implicated in the key pathological process of fibrosis. In this review, we summarize the current status of knowledge regarding the role of CCN proteins involved in the pathogenesis of fibrosis diseases in detail. Furthermore, we highlight some of the underlying interaction mechanisms of CCN protein acting in fibrosis that helps to develop new drugs and determine appropriate clinical strategies for fibrotic diseases.

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Regulation of the CCN genes by vitamin D: A possible adjuvant therapy in the treatment of cancer and fibrosis

Cited by 6 publications

References 123 publications

CCN family of proteins: critical modulators of the tumor cell microenvironment

CCN family of proteins: critical modulators of the tumor cell microenvironment

Circadian control of the secretory pathway is a central mechanism in tissue homeostasis

Emerging role of CCN family proteins in fibrosis

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