Regulation of <i>Cyr61/CCN1</i> gene expression through RhoA GTPase and p38MAPK signaling pathways

Han, Ji Soo; Macarak, Edward J.; Rosenbloom, Joel; Chung, Kwang Chul; Chaqour, Brahim

doi:10.1046/j.1432-1033.2003.03723.x

Cited by 74 publications

(92 citation statements)

References 61 publications

(72 reference statements)

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“…TRANSFAC analysis (Wingender et al, 2000) revealed that the AP-1-like element in the Cyr61/CCN1 gene promoter is a variant of the AP-1 consensus sequence (base À821 to À828) in which a single-base substitution of the center nucleotide has occurred (5 0 -TGACTCAG-3 0 ). Earlier studies showed that the AP-1 element has a critical role in regulating CCN1 promoter activity and hence CCN1 expression is tightly regulated through AP-1 transcription factors (Han et al, 2003). Mutation of the distal AP-1 element in the CCN1 promoter-reporter construct or overexpression of a dominant-negative AP-1 inhibitor reduced sphingosine 1-phosphate-induced CCN1 promoter activity by nearly 45% (Han et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Earlier studies showed that the AP-1 element has a critical role in regulating CCN1 promoter activity and hence CCN1 expression is tightly regulated through AP-1 transcription factors (Han et al, 2003). Mutation of the distal AP-1 element in the CCN1 promoter-reporter construct or overexpression of a dominant-negative AP-1 inhibitor reduced sphingosine 1-phosphate-induced CCN1 promoter activity by nearly 45% (Han et al, 2003). We documented that SARI exerts a cancer-specific antitumor effect by inhibiting AP-1 binding activity .…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1

Dash

Lee

et al. 2010

Oncogene

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Enhanced expression of the CCN family of secretory integrin-binding proteins correlates with many essential components of the cancerous state, including tumor cell adhesion, proliferation, invasion and migration. Consequently, CCN1 expression is elevated in various cancers, including breast cancer, and its expression directly correlates with poor patient prognosis. Using subtraction-hybridization, combined with induction of cancer cell terminal differentiation, we cloned SARI (suppressor of activator protein (AP)-1, regulated by interferon (IFN)), an IFN-b-inducible, potent tumor suppressor gene that exerts cancer-selective growth inhibitory effects. Forced expression of SARI using an adenovirus (Ad.SARI) inhibits AP-1 function and downregulates CCN1 expression in multiple cancer lineages, resulting in a profound inhibition in anchorage-independent cell growth and tumor cell invasion. Overexpression of SARI reduces CCN1-promoter activity through inhibition of AP-1 binding. Accordingly, SARI selectively blocks expression of the transformed state in rat embryo fibroblast cells that stably overexpress c-Jun. These results illustrate that SARI inhibits AP-1 transactivating factor binding to the ciselement of the CCN1 promoter, possibly through its interaction with c-Jun. Overall, SARI can directly inhibit CCN1-induced transformation by inhibiting the transcription of CCN1, as well as indirectly by inhibiting the expression of c-Jun (and hence blocking AP-1 activity). In these contexts, transformed cells 'addicted' to AP-1 activity are rendered susceptible to SARI-mediated inhibition of expression of the transformed phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1

Dash

Lee

et al. 2010

Oncogene

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“…In addition, CCN1 is commonly overexpressed in GBMs, and its overexpression correlates with short survival time of GBM patients [22]. S1P has been shown to induce expression of CCN1 in smooth muscle cells [23]. We therefore, examined CCN1 protein levels in S1P receptor over-and underexpressing cell lines (Fig.…”

Section: Role Of Ccn1 In S1p-stimulated Invasionmentioning

confidence: 99%

Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness

Young

Brocklyn

2007

Experimental Cell Research

110

116

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Sphingosine-1-Phosphate (S1P) is a bioactive lipid that signals through a family of five G proteincoupled receptors, termed S1P 1-5 . S1P stimulates growth and invasiveness of glioma cells, and high expression levels of the enzyme that forms S1P, sphingosine kinase-1, correlate with short survival of glioma patients. In this study we examined the mechanism of S1P stimulation of glioma cell proliferation and invasion by either overexpressing or knocking down, by RNA interference, S1P receptor expression in glioma cell lines. S1P 1 , S1P 2 and S1P 3 all contribute positively to S1P-stimulated glioma cell proliferation, with S1P 1 being the major contributor. Stimulation of glioma cell proliferation by these receptors correlated with activation of ERK MAP kinase. S1P 5 blocks glioma cell proliferation, and inhibits ERK activation. S1P 1 and S1P 3 enhance glioma cell migration and invasion. S1P 2 inhibits migration through Rho activation, Rho kinase signaling and stress fiber formation, but unexpectedly, enhances glioma cell invasiveness by stimulating cell adhesion. S1P 2 also potently enhances expression of the matricellular protein CCN1/Cyr61, which has been implicated in tumor cell adhesion, and invasion as well as tumor angiogenesis. A neutralizing antibody to CCN1 blocked S1P 2 -stimulated glioma invasion. Thus, while S1P 2 decreases glioma cell motility, it may enhance invasion through induction of proteins that modulate glioma cell interaction with the extracellular matrix.

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“…Activation of the human CCN1 promoter was found to be regulated by CREB and activator protein 1 (AP-1) in sphingosine-stimulated smooth muscle cells (31) and by HIF and AP-1 following hypoxia in melanoma cells (21,22). The mouse CCN1 promoter was found to be activated by serum components via a serum response element at position À2 kb and an Egr binding site at position À48 bp (32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

Meyuhas¹,

Pikarsky²,

Tavor³

et al. 2008

Molecular Cancer Research

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Hypoxia is a prominent feature of solid tumors known to contribute to malignant progression and therapeutic resistance. Cancer cells adapt to hypoxia using various pathways, allowing tumors to thrive in a low oxygen state. Induction of new blood vessel formation via the secretion of proangiogenic factors is one of the main adaptive responses engaged by tumor cells under hypoxic conditions. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that plays a pivotal role in mediating such responses. In addition, several other transcription factors have also been implicated in hypoxic gene regulation, either independently or in cooperation with HIF-1. In this work, we show that the expression of the angiogenesis-related, immediate early gene CCN1 (formerly known as CYR61), considered to be involved in tumor growth and invasiveness, is enhanced upon hypoxia stress primarily in a protein kinase A and cyclic AMP-responsive element binding protein (CREB) and CRE -dependent manner in various cell lines. The hypoxia-mediated activation of the CCN1 promoter is independent of HIF-1 and HIF-2, as shown by small interfering RNA knockdown. We identify the cis element in the mouse CCN1 promoter responsible for CREB binding to be one of two partial CRE sites present in the promoter. Moreover, we report for the first time that CREB-mediated CCN1 transcription is enhanced in hypoxic regions of tumors in vivo. Identifying and characterizing the molecular mechanisms that govern the response of tumors to hypoxia may be instrumental to identify the tumors that will respond favorably to inhibition of angiogenesis and thus lead to the development of treatments that could complement hypoxia-inducing treatment modalities.

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Regulation of Cyr61/CCN1 gene expression through RhoA GTPase and p38MAPK signaling pathways

Cited by 74 publications

References 61 publications

Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1

Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1

Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness

A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells

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