Dataset Information

Involvement of S100A14 protein in cell invasion by affecting expression and function of matrix metalloproteinase (MMP)-2 via p53-dependent transcriptional regulation.

ABSTRACT: S100 proteins have been implicated in tumorigenesis and metastasis. As a member of S100 proteins, the role of S100A14 in carcinogenesis has not been fully understood. Here, we showed that ectopic overexpression of S100A14 promotes motility and invasiveness of esophageal squamous cell carcinoma cells. We investigated the underlying mechanisms and found that the expression of matrix metalloproteinase (MMP)-2 is obviously increased after S100A14 gene overexpression. Inhibition of MMP2 by a specific MMP2 inhibitor at least partly reversed the invasive phenotype of cells overexpressing S100A14. By serendipity, we found that S100A14 could affect p53 transactivity and stability. Thus, we further investigated whether the effect of MMP2 by S100A14 is dependent on p53. A series of biochemical assays showed that S100A14 requires functional p53 to affect MMP2 transcription, and p53 potently transrepresses the expression of MMP2. Finally, RT-quantitative PCR analysis of human breast cancer specimens showed a significant correlation between S100A14 mRNA expression and MMP2 mRNA expression in cases with wild-type p53 but not in cases with mutant p53. Collectively, our data strongly suggest that S100A14 promotes cell motility and invasiveness by regulating the expression and function of MMP2 in a p53-dependent manner.

SUBMITTER: Chen H

PROVIDER: S-EPMC3366841 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Involvement of S100A14 protein in cell invasion by affecting expression and function of matrix metalloproteinase (MMP)-2 via p53-dependent transcriptional regulation.

Chen Hongyan H Yuan Yi Y Zhang Chunpeng C Luo Aiping A Ding Fang F Ma Jianlin J Yang Shouhui S Tian Yanyan Y Tong Tong T Zhan Qimin Q Liu Zhihua Z

The Journal of biological chemistry 20120326 21

S100 proteins have been implicated in tumorigenesis and metastasis. As a member of S100 proteins, the role of S100A14 in carcinogenesis has not been fully understood. Here, we showed that ectopic overexpression of S100A14 promotes motility and invasiveness of esophageal squamous cell carcinoma cells. We investigated the underlying mechanisms and found that the expression of matrix metalloproteinase (MMP)-2 is obviously increased after S100A14 gene overexpression. Inhibition of MMP2 by a specific ...[more]

PMID: 22451655

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Project description:BackgroundThe role of connective tissue growth factor (CTGF/CCN2) in pathological angiogenesis in the retina is unknown.ResultsCTGF/CCN2 stimulates retinal neovascularization through transactivation of p53 target genes such as matrix metalloproteinase (MMP)-2.ConclusionCTGF/CCN2 effects on abnormal vessel formation in the retina are mediated by p53 and MMP-2.SignificanceCTGF/CCN2 and its downstream effectors are potential targets in the development of new antiangiogenic treatments. Pathological angiogenesis in the retina is driven by dysregulation of hypoxia-driven stimuli that coordinate physiological vessel growth. How the various components of the neovascularization signaling network are integrated to yield pathological changes has not been defined. Connective tissue growth factor (CTGF/CCN2) is an inducible matricellular protein that plays a major role in fibroproliferative disorders. Here, we show that CTGF/CCN2 was dynamically expressed in the developing murine retinal vasculature and was abnormally increased and localized within neovascular tufts in the mouse eye with oxygen-induced retinopathy. Consistent with its propitious vascular localization, ectopic expression of the CTGF/CCN2 gene further accelerated neovascularization, whereas lentivirus-mediated loss-of-function or -expression of CTGF/CCN2 harnessed ischemia-induced neovessel outgrowth in oxygen-induced retinopathy mice. The neovascular effects of CTGF/CCN2 were mediated, at least in part, through increased expression and activity of matrix metalloproteinase (MMP)-2, which drives vascular remodeling through degradation of matrix and non matrix proteins, migration and invasion of endothelial cells, and formation of new vascular patterns. In cultured cells, CTGF/CCN2 activated the MMP-2 promoter through increased expression and tethering of the p53 transcription factor to a highly conserved p53-binding sequence within the MMP-2 promoter. Concordantly, the neovascular effects of CTGF/CCN2 were suppressed by p53 inhibition that culminated in reduced enrichment of the MMP-2 promoter with p53 and decreased MMP-2 gene expression. Our data identified new gene targets and downstream effectors of CTGF/CCN2 and provided the rational basis for targeting the p53 pathway to curtail the effects of CTGF/CCN2 on neovessel formation associated with ischemic retinopathy.

Dataset Information

Involvement of S100A14 protein in cell invasion by affecting expression and function of matrix metalloproteinase (MMP)-2 via p53-dependent transcriptional regulation.

Publications

Involvement of S100A14 protein in cell invasion by affecting expression and function of matrix metalloproteinase (MMP)-2 via p53-dependent transcriptional regulation.

Similar Datasets

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