CCN5, a secreted protein, localizes to the nucleus

Wiesman, Kristina C.; Lan, Wei; Baughman, Cassandra; Russo, Joshua W.; Gray, Mark R.; Castellot, John J.

doi:10.1007/s12079-010-0087-x

Cited by 23 publications

(19 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, it has also been reported that CCN6/WISP-3 can localize to the nuclei of breast cancer cells (22). Finally, it has been reported that CCN2 and CCN5 are detected in the cytoplasmic compartment as well as the nuclear compartment in many rodent embryonic and adult tissues as well as in fetal human tissues (20,27,50). Collectively, these data are suggestive of diverse functions for the CCN family, including nuclear function for several of its members.…”

mentioning

confidence: 86%

CCN5, a Novel Transcriptional Repressor of the Transforming Growth Factor β Signaling Pathway

Sabbah

Prunier

Ferrand

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

CCN5 is a member of the CCN (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family and was identified as an estrogen-inducible gene in estrogen receptor-positive cell lines. However, the role of CCN5 in breast carcinogenesis remains unclear. We report here that the CCN5 protein is localized mostly in the cytoplasm and in part in the nucleus of human tumor breast tissue. Using a heterologous transcription assay, we demonstrate that CCN5 can act as a transcriptional repressor presumably through association with histone deacetylase 1 (HDAC1). Microarray gene expression analysis showed that CCN5 represses expression of genes associated with epithelial-mesenchymal transition (EMT) as well as expression of key components of the transforming growth factor ␤ (TGF-␤) signaling pathway, prominent among them TGF-␤RII receptor. We show that CCN5 is recruited to the TGF-␤RII promoter, thereby providing a mechanism by which CCN5 restricts transcription of the TGF-␤RII gene. Consistent with this finding, CCN5, we found, functions to suppress TGF-␤-induced transcriptional responses and invasion that is concomitant with EMT. Thus, our data uncovered CCN5 as a novel transcriptional repressor that plays an important role in regulating tumor progression functioning, at least in part, by inhibiting the expression of genes involved in the TGF-␤ signaling cascade that is known to promote EMT.CCN5 (previously known as WISP-2) is a 29-kDa protein member of the connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family (2, 5, 23). The CCN family is composed of six members grouped on the basis of similar structural analogies (7). CCN proteins appear to play important roles in several biological processes, including cell growth, adhesion, and migration as well as numerous endocrine-regulated functions (9,39,41). CCN proteins encompass four structural domains: an insulin-like growth factor-binding protein (IGF-BP) domain, a von Willebrand factor type C (VWC) domain, a thrombospondin (TSP-1) domain, and a cysteine knot (CT) domain reported to act as a potential proliferation module (29). Although the physiological function of CCN5 is not well defined, its domain structure suggests that its function may be different from that of other members of the CCN family. CCN5 contains only three structural domains and lacks the CT domain (7,8,35). It has been shown that CCN5 suppresses proliferation and its expression is reduced in cancers (14,31,35). Previously, we showed that upon hormone binding, the estrogen receptor (ER) directly regulates the ccn5 gene in all ER-positive breast cancer cell lines tested (17). Moreover, we found that CCN5 knockdown not only induced estradiol-independent growth of these cells, owing to a loss of estrogen receptor ␣ (ER␣) expression, but also promoted epithelial-mesenchymal transition (EMT) (18), a process involved in tumor invasiveness and metastasis (13,43,46,51).Consistent with its role in tumor progression, our recent studies have shown that CCN5 is ...

show abstract

mentioning

confidence: 86%

CCN5, a Novel Transcriptional Repressor of the Transforming Growth Factor β Signaling Pathway

Sabbah

Prunier

Ferrand

et al. 2011

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…In a secretome analysis of human SAT, comparing lean and obese patients, WISP2 came out as a top candidate being upregulated in obesity (66). WISP2 is most highly expressed in SAT, primarily in MSCs, fibroblasts, and preadipocytes, and acts both intra-and extracellularly (87,313). In addition, our laboratory has found that secreted WISP2 has the potential to enhance the proliferation of MSCs in both white (WAT) and brown adipose tissue (BAT) (88).…”

Section: Wisp2 a Secreted Wnt-associatedmentioning

confidence: 99%

Impaired Adipogenesis and Dysfunctional Adipose Tissue in Human Hypertrophic Obesity

Hammarstedt

Gogg

Hedjazifar

et al. 2018

Physiological Reviews

328

256

View full text Add to dashboard Cite

The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor cells. When inadequate, this leads to a hypertrophic expansion of the cells with increased inflammation, insulin resistance, and a dysfunctional prolipolytic tissue. Epi-/genetic factors regulate SAT adipogenesis and genetic predisposition for type 2 diabetes is associated with markers of an impaired SAT adipogenesis and development of hypertrophic obesity also in nonobese individuals. We here review mechanisms for the adipose precursor cells to enter adipogenesis, emphasizing the role of bone morphogenetic protein-4 (BMP-4) and its endogenous antagonist gremlin-1, which is increased in hypertrophic SAT in humans. Gremlin-1 is a secreted and a likely important mechanism for the impaired SAT adipogenesis in hypertrophic obesity. Transiently increasing BMP-4 enhances adipogenic commitment of the precursor cells while maintained BMP-4 signaling during differentiation induces a beige/brown oxidative phenotype in both human and murine adipose cells. Adipose tissue growth and development also requires increased angiogenesis, and BMP-4, as a proangiogenic molecule, may also be an important feedback regulator of this. Hypertrophic obesity is also associated with increased lipolysis. Reduced lipid storage and increased release of FFA by hypertrophic SAT are important mechanisms for the accumulation of ectopic fat in the liver and other places promoting insulin resistance. Taken together, the limited expansion and storage capacity of SAT is a major driver of the obesity-associated metabolic complications.

show abstract

“…Given the capacity of matricellular proteins to bind other ECM components, their putative roles as chaperones for these molecules and perhaps growth factors are reasonable ( Chlenski et al, 2004 ; Emerson et al, 2006 ). Some matricellular proteins have also been identified in nuclear compartments (SPARC, CCN5, amino-domain truncated CCN3) ( Gooden et al, 1999 ; Planque et al, 2006 ; Wiesman et al, 2010 ), although the nuclear roles of matricellular proteins remain unclear. Nonetheless, the possibility that matricellular proteins act as intracellular targeting or transport molecules warrants further investigation.…”

Section: Members Of the Matricellular Familymentioning

confidence: 99%

Revisiting the matricellular concept

Murphy-Ullrich

Sage²

2014

Matrix Biology

341

274

View full text Add to dashboard Cite

The concept of a matricellular protein was first proposed by Paul Bornstein in the mid-1990s to account for the non-lethal phenotypes of mice with inactivated genes encoding thrombospondin-1, tenascin-C, or SPARC. It was also recognized that these extracellular matrix proteins were primarily counter or de-adhesive. This review reappraises the matricellular concept after nearly two decades of continuous investigation. The expanded matricellular family as well as the diverse and often unexpected functions, cellular location, and interacting partners/receptors of matricellular proteins are considered. Development of therapeutic strategies that target matricellular proteins are discussed in the context of pathology and regenerative medicine.

show abstract

CCN5, a secreted protein, localizes to the nucleus

Cited by 23 publications

References 18 publications

CCN5, a Novel Transcriptional Repressor of the Transforming Growth Factor β Signaling Pathway

CCN5, a Novel Transcriptional Repressor of the Transforming Growth Factor β Signaling Pathway

Impaired Adipogenesis and Dysfunctional Adipose Tissue in Human Hypertrophic Obesity

Revisiting the matricellular concept

Contact Info

Product

Resources

About