Combinatorial Interactions of p53, Activating Protein-2, and YB-1 with a Single Enhancer Element Regulate Gelatinase A Expression in Neoplastic Cells

Mertens, Peter R.; Steinmann, Karin; Alfonso-Jaume, Maria A.; En‐Nia, Abdelaziz; Sun, Yi; Lovett, David H.

doi:10.1074/jbc.m200445200

Cited by 57 publications

(56 citation statements)

References 41 publications

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“…43 AP-2a has also been recently reported to interact directly with p53 and to augment p53 transcriptional activation. 33 This finding would be in line with our data that Bax, a classical proapoptotic target gene of p53, is increased after overexpression of AP-2a. However, our observation that pifithrin-a, an inhibitor of p53 transcriptional activation, did inhibit neither AP-2a-induced caspase activation nor apoptosis (data not shown) would argue against an essential role of p53.…”

Section: Discussionsupporting

confidence: 89%

“…Proteolytic activity of caspases was significantly increased 3 days after infection with Ad-AP-2a reaching a plateau on day 4. Activation of caspases by AP-2a was apparently independent from transcription factor p53, a central regulator of apoptosis, 33 since a similar extent of caspase activation was observed in the presence of pifithrin-a, an inhibitor interfering with p53-mediated transactivation. 34 In order to identify apoptosisrelated target genes of AP-2a in cardiomyocytes, we studied the mRNA levels of Fas (CD95), Bcl-x, Fas ligand (FasL), caspase-1, caspase-2, caspase-3, Bax and Bcl-2 in Ad-AP2a-and Ad-Ctr-infected cardiomyocytes using RNase protection assays ( Figure 5).…”

Section: Adenovirus-mediated Overexpression Of Ap-2a Triggers Apoptosmentioning

confidence: 77%

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Transcription factor AP-2α triggers apoptosis in cardiac myocytes

et al. 2004

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Idiopathic-dilated cardiomyopathy (IDC) is a common primary myocardial disease of unknown etiology associated with apoptosis, cardiac dilatation, progressive heart failure and increased mortality. An elevation of the transcription factor activator protein 2a (AP-2a) is involved in vertebrate embryonic development and oncogenesis. Here, we show that AP-2a protein is expressed in the human heart and increased in human failing myocardium with IDC. Adenovirusmediated overexpression of human AP-2a triggered apoptosis and increased mRNA levels of Bcl-2 family members Bax and Bcl-x in rat cardiomyocytes. Immunohistological analysis of human myocardium revealed an increased percentage of AP-2a-positive nuclei in IDC and, interestingly, a colocalization of AP-2a-positive but not -negative cells with a caspasecleaved fragment of poly(ADP-ribose)polymerase. We suggest AP-2a as a novel cardiac regulator implicated in the activation of apoptosis in IDC.

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Section: Discussionsupporting

confidence: 89%

Section: Adenovirus-mediated Overexpression Of Ap-2a Triggers Apoptosmentioning

confidence: 77%

Transcription factor AP-2α triggers apoptosis in cardiac myocytes

et al. 2004

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“…In contrast to the previously well characterized 5Ј AP-1͞RE-1 region (7,8,10), there are no studies of transcriptional regulation in the MMP-2 intron, and we consequently identified ischemia-induced expression of NFATc2 and its binding to the 3Ј aspect of the first intron. Our findings collectively suggest that NFATc2 mediates MMP-2 transactivation via intronic regulation of the MMP-2 promoter.…”

Section: Discussionmentioning

confidence: 49%

“…Binding of the transcription factors YB-1, AP-2, and p53 to an enhancer element designated RE-1, located at Ϫ1,322 bp relative to the translation start site in the rat MMP-2 promoter, mediates transcription in mesangial (7) and tumor cells (8). In contrast, the proximal Sp-1 and AP-2 sites at Ϫ90 to Ϫ50 bp are sufficient for constitutive MMP-2 transcription in astrocytoma cell lines (9).…”

mentioning

confidence: 99%

Intronic regulation of matrix metalloproteinase-2 revealed by in vivo transcriptional analysis in ischemia

Lee

Dahi²,

Mahimkar³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Matrix metalloproteinase-2 (MMP-2) plays an essential role in angiogenesis and arteriogenesis, two processes critical to restoration of tissue perfusion after ischemia. MMP-2 expression is increased in tissue ischemia, but the responsible mechanisms remain unknown. We studied the transcriptional activation of the MMP-2 gene in a model of hindlimb ischemia by using various MMP-2-lacZ reporter mice and chromatin immunoprecipitation. MMP-2 activity and mRNA were increased after hindlimb ischemia. Mice with targeted deletion of MMP-2 had impaired restoration of perfusion and a high incidence of limb gangrene, indicating that MMP-2 plays a critical role in ischemia-induced revascularization. Ischemia induced the expression and binding of c-Fos, c-Jun, JunB, FosB, and Fra2 to a noncanonical activating protein-1 (AP-1) site present in the MMP-2 promoter and decreased binding of the transcriptional repressor JunD. Ischemia also activated the expression and binding of p53 to an adjacent enhancer site (RE-1) and increased expression and binding of nuclear factor of activated T-cells-c2 to consensus sequences within the first intron. Deletion of either the 5 AP-1͞ RE-1 region of the promoter or substitution of the first intron abolished ischemia-induced MMP-2 transcription in vivo. Thus, AP-1 transcription factors and intronic activation by nuclear factor of activated T-cells-c2 act in concert to drive ischemia-induced MMP-2 transcription. These findings define a critical role for MMP-2 in ischemia-induced revascularization and identify both previously uncharacterized regulatory elements within the MMP-2 gene and the cognate transcription factors required for MMP-2 activation in vivo after tissue ischemia.angiogenesis ͉ gelatinase ͉ gene expression ͉ skeletal muscle ͉ transcription factor T issue ischemia secondary to arterial ischemia remains a major source of morbidity and mortality. Despite their importance, the cellular and molecular mechanisms that drive transcription of the genes essential for reversal of ischemia in vivo remain largely undefined. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes important in tissue remodeling and repair. MMP-2 has been implicated in the collateral arterial enlargement that occurs in response to tissue ischemia (1), and its expression is essential for retinal and tumor-induced angiogenesis (2, 3). MMP-2 (gelatinase A) can cleave most extracellular matrix proteins, including collagen, and can proteolytically activate other proenzymes, such as MMP-9. The lack of MMP-14 (membrane-type 1-MMP), the cell surface protease that cleaves proMMP-2 to its active form, abolishes postnatal angiogenesis (4), and targeted deletion of MMP-9 impairs revascularization after hindlimb ischemia (5). Experimental hindlimb ischemia increases expression of MMP-2, MMP-9, and MMP-14 (6). Despite the potential importance of MMP-2 in ischemia-induced angiogenesis and arteriogenesis, the role of MMP-2 in this process and the transcriptional regulatory mechanisms that regulate MMP-2 in tissue is...

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“…Several groups have studied the transcriptional regulation of MMP-2 by other transcription factors, such as p53 (Harendza et al, 1995;Bian and Sun 1997;Mertens et al, 2002, Yan et al, 2002. A highly conserved enhancer element mapped between bp À1657 and À1619 in the human 5 0 -flanking region (denoted r2), and between bp À1048 and 1008 in the rat (denoted RE-1) (Bian and Sun 1997;Mertens et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis

et al. 2004

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The expression of matrix metalloproteinase-2 (MMP-2) has been linked with tumor invasion, angiogenesis, and metastasis. However, the molecular basis for MMP-2 overexpression in tumor cells remains unclear. In this study, by using K-1735 melanoma system, we demonstrated that highly metastatic C4, M2, and X21 tumor cells express elevated MMP-2 mRNA and enzymatic activity, whereas poorly metastatic C10, C19, and C23 tumor cells express much lower levels. Moreover, a concomitant elevated Stat3 activity has been detected in these metastatic tumor cells that overexpress MMP-2. Transfection of constitutively activated Stat3 into poorly metastatic C23 tumor cells directly activated the MMP-2 promoter, whereas the expression of a dominant-negative Stat3 in highly metastatic C4 tumor cells inhibited the MMP-2 promoter. A high-affinity Stat3-binding element was identified in the MMP-2 promoter and Stat3 protein bound directly to the MMP-2 promoter. Blockade of activated Stat3 through expression of a dominant-negative Stat3 significantly suppressed MMP-2 expression in the metastatic tumor cells. Therefore, overexpression of MMP-2 in the metastatic melanoma cells can be attributed to elevated Stat3 activity, and Stat3 upregulates the transcription of MMP-2 through direct interaction with the MMP-2 promoter. Furthermore, blockade of activated Stat3 in highly metastatic C4 cells significantly suppressed the invasiveness of the tumor cells, inhibited tumor growth, and prevented metastasis in nude mice. Collectively, these studies suggest that Stat3 signaling directly regulates MMP-2 expression, tumor invasion, and metastasis, and that Stat3 activation might be a crucial event in the development of metastasis.

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Combinatorial Interactions of p53, Activating Protein-2, and YB-1 with a Single Enhancer Element Regulate Gelatinase A Expression in Neoplastic Cells

Cited by 57 publications

References 41 publications

Transcription factor AP-2α triggers apoptosis in cardiac myocytes

Transcription factor AP-2α triggers apoptosis in cardiac myocytes

Intronic regulation of matrix metalloproteinase-2 revealed by in vivo transcriptional analysis in ischemia

Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis

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