Overexpression of Connective Tissue Growth Factor Gene Induces Apoptosis in Human Aortic Smooth Muscle Cells

Hishikawa, Keiichi; Oemar, Barry S.; Tanner, Felix C.; Nakaki, Toshio; Fujii, Tomoko; Lüscher, Thomas F.

doi:10.1161/01.cir.100.20.2108

Cited by 90 publications

(57 citation statements)

References 31 publications

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“…In this regard, overexpressed CTGF/Hcs24 was found to accumulate around the central mitotic machinery in Cos-7 cells, did not induce cell growth, and rather acted as an antimitotic agent (Kubota et al, 2000a). Because CTGF/ Hcs24 is reported to be related to apoptosis in human breast cancer cell line (Hishikawa et al, 1999b) and aortic smooth muscle cells (Hishikawa et al, 1999a) and because the binding of CTGF/Hcs24 to growth cartilage cells decreases as the cells differentiate into hypertrophic ones, the predominant expression of CTGF/ Hcs24 in hypertrophic chondrocytes might also induce restriction of cell proliferation, maybe even apoptosis, of hypertrophic chondrocytes by acting intracellularly, in addition to exerting its paracrine actions on prehypertrophic and proliferating chondrocytes, endothelial cells, and osteoblasts (Fig. 3).…”

Section: Intracellular Localization Of Ctgf/hcs24mentioning

confidence: 99%

Role of CTGF/HCS24/ecogenin in skeletal growth control

Takigawa¹,

Nakanishi²,

Kubota³

et al. 2003

Journal Cellular Physiology

173

185

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Connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24) is a multifunctional growth factor for chondrocytes, osteoblasts, and vascular endothelial cells. CTGF/Hcs24 promotes the proliferation and maturation of growth cartilage cells and articular cartilage cells in culture and hypertrophy of growth cartilage cells in culture. The factor also stimulates the proliferation and differentiation of cultured osteoblastic cells. Moreover, CTGF/ Hcs24 promotes the adhesion, proliferation, and migration of vascular endothelial cells, as well as induces tube formation by the cells and strong angiogenesis in vivo. Because angiogenesis is critical for the replacement of cartilage with bone at the final stage of endochondral ossification and because gene expression of CTGF/ Hcs24 predominates in hypertrophic chondrocytes in the physiological state, a major physiological role for this factor should be the promotion of the entire process of endochondral ossification, with the factor acting on the above three types of cells as a paracrine factor. Thus, CTGF/Hcs24 should be called ''ecogenin: endochondral ossification genetic factor.'' In addition to hypertrophic chondrocytes, osteoblasts activated by various stimuli including wounding also express a significantly high level of CTGF/Hcs24. These findings in conjunction with in vitro findings about osteoblasts mentioned above suggest the involvement of CTGF/Hcs24 in intramembranous ossification and bone modeling/remodeling. Because angiogenesis is also critical for intramembranous ossification and bone remodeling, CTGF/ Hcs24 expressed in endothelial cells activated by various stimuli including wounding may also play important roles in direct bone formation. In conclusion, although the most important physiological role of CTGF/Hcs24 is ecogenin action, the factors also play important roles in skeletal growth and modeling/remodeling via its direct action on osteoblasts under both physiological and pathological conditions.

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Section: Intracellular Localization Of Ctgf/hcs24mentioning

confidence: 99%

Role of CTGF/HCS24/ecogenin in skeletal growth control

Takigawa¹,

Nakanishi²,

Kubota³

et al. 2003

Journal Cellular Physiology

173

185

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“…2A). This cluster also includes CTGF, which promotes fibroblast proliferation and extracellular matrix formation and has been implicated in liver fibrosis (48) and TGF-␤ 1 -induced apoptosis in MCF-7 and human aortic smooth muscle cells (49,50). The CTGF gene contains a TGF-␤ 1 -responsive element and is strongly up-regulated in MCF-7 cells (which do not normally express CTGF mRNA) during TGF-␤ 1 -induced apoptosis (49).…”

Section: Confirmation Of Selected Gene Changes By Rt-pcr-mentioning

confidence: 99%

Characterization of the Transforming Growth Factor-β1-induced Apoptotic Transcriptome in FaO Hepatoma Cells

Coyle¹,

Freathy

Gant

et al. 2003

Journal of Biological Chemistry

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We have previously shown that transforming growth factor-␤ 1 (TGF-␤ 1 )-induced apoptosis in FaO hepatoma cells is mediated by cytochrome c release, apoptosome formation, and caspase activation. Although TGF-␤ 1 acts via the SMAD signaling pathway to initiate de novo gene transcription, little is known about the downstream gene targets that are involved in the regulation of apoptosis. Therefore, in this study, we used in-house microarrays (ϳ5500 genes) to identify pathway-specific gene clustering in TGF-␤ 1 -treated cells. A total of 142 genes showed time-dependent changes in expression during TGF-␤ 1 -induced apoptosis. The polycaspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone, which, on its own, had no effect on gene transcription, blocked TGF-␤ 1 -induced cell death and significantly altered the expression of 261 genes, including 185 downregulated genes. Cluster analysis identified up-regulation of early response genes (0-4 h) encoding for the extracellular matrix and cytoskeleton, including the pro-apoptotic CTGF gene, and delayed response genes (8-16 h), including pro-apoptotic genes. A second delayed response cluster (44 genes) was also observed when TGF-␤ 1 -induced caspase activation was blocked by benzyloxycarbonyl-VAD-fluoromethyl ketone. This cluster included genes encoding stress-related proteins (e.g. Jun, ATF3, TAB1, and TANK), suggesting that their up-regulation may be in response to secondary necrosis. Finally, we identified an early response set of nine down-regulated genes that are involved in antioxidant defense. We propose that the regulation of these genes by TGF-␤ 1 could provide a molecular mechanism for the observed elevation in reactive oxygen species after TGF-␤ 1 treatment and may represent the primary mechanism through which TGF-␤ 1 initiates apoptosis.

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“…Fas is a cell surface receptor which, upon activation by a ligand, induces the Fas-associated death pathway (FADD) [15]. CTGF may be involved in the induction or inhibition of the FADD pathway by way of its inactivation of the Smad inhibitor SMAD7 [43], or through its general association with TGFb signaling [9,17].…”

Section: Introductionmentioning

confidence: 99%

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

Joyner

Aboulafia

Damron

et al. 2008

Clin Orthop Relat Res

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Modulation of apoptosis may influence sarcoma pathogenesis and/or aggressiveness. The Fas death pathway, mediated by FasL or TGFb, is one of two apoptotic pathways. Recent studies report that EGF can modulate TGFb and/or FasL expression/activity; thus, EGF has the potential to influence activation of the Fas pathway. EGF is not always detectable in mesenchymal tumors; therefore, we hypothesized EGF would define which Fas ligand predominates. We assayed 57 surgically removed human sarcomas for 10 genes involved in the Fas pathway. Skeletal muscle biopsies from eight patients served as controls. Sample transcripts were detected by real-time RT-PCR. We attempted to identify relevant predictor variables. The 57 sarcomas were segregated into two categories defined by EGF mRNA content: (1) 23 tumors with EGF concentrations that approximated muscle EGF transcript levels (high-EGF tumors); and (2) 34 tumors that either lacked EGF mRNA, or whose mRNA levels were very low and frequently undetected by PCR (low-EGF tumors). TGFb1 expression best predicted Fas transcript concentrations in the 34 low-EGF sarcomas, while FasL predicted Fas mRNA levels in the remaining 23 high-EGF sarcomas. The results suggest ligand activity in the Fas death pathway correlates with EGF transcription in sarcomas.

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Overexpression of Connective Tissue Growth Factor Gene Induces Apoptosis in Human Aortic Smooth Muscle Cells

Cited by 90 publications

References 31 publications

Role of CTGF/HCS24/ecogenin in skeletal growth control

Role of CTGF/HCS24/ecogenin in skeletal growth control

Characterization of the Transforming Growth Factor-β1-induced Apoptotic Transcriptome in FaO Hepatoma Cells

Fas Death Pathway in Sarcomas Correlates with Epidermal Growth Factor Transcription

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