Loss of Activator Protein-2α Results in Overexpression of Protease-activated Receptor-1 and Correlates with the Malignant Phenotype of Human Melanoma

Tellez, Carmen S.; McCarty, Marya F.; Ruiz, Maribelís; Bar‐Eli, Menashe

doi:10.1074/jbc.m309159200

Cited by 105 publications

(123 citation statements)

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“…In-contrast, a direct correlation was established between the expression of specificity protein 1(Sp1) and aggressive melanoma cells. While demonstrating that AP-2 and Sp1 bind to a complex region within hPar 1 promoter, in a mutually exclusive manner, this study suggested that loss of AP-2 in metastatic cells alters the AP-2/Sp1 ratio, resulting in the overexpression of hPar 1 in metastatic melanoma (16). Altogether, these observations strengthen the notion that specific transcription factors and tumor suppressors may delicately regulate the overexpression of hPar 1 gene at the appropriate given cancer context.…”

Section: Molecular Mechanism Underlying Par 1 Gene Over-expression Insupporting

confidence: 72%

PAR₁ plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

et al. 2011

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SummaryProtease-activated receptor1 (PAR 1 ) is the first and prototype member of an established PAR family comprising four members. The role of PAR 1 in tumor biology has been established, and is characterized by a consistent direct correlation between overexpression of its levels and epithelial tumor aggressiveness. We have found that high expression of the human Par 1 (hPar 1 ) gene in epithelial tumors is controlled largely at the transcriptional level. This led us to assign Egr-1, a transcription activator, as an inducer of hPar 1 , and p53, a tumor suppressor gene, as an inhibitor, both acting to achieve fine tuning of hPar 1 in prostate carcinoma. High PAR 1 levels maintain prosurvival signals in tumor cells while silencing or ablation of the gene induce apoptosis. Studies of our hPar 1 transgenic mice, which overexpress hPar 1 in the mammary glands, revealed a novel PAR 1 -induced b-catenin stabilization function. The components connecting PAR 1 to b-catenin stabilization have been determined, assigning at first G a13 as a selective immediate component. The PAR 1 -G a13 axis recruits disheveled (DVL), an upstream signaling partner of the canonical Wnt signaling pathway. Silencing of DVL by siRNA-DVL potently abrogates PAR 1 -induced b-catenin stabilization, demonstrating its critical role in the process. We, thus, propose that transcriptional regulation of hPar 1 gene over expression in epithelia malignancies initiates a novel signaling pathway, directly connecting to b-catenin stabilization, a core event in both tumorigenesis and developmental processes.

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Section: Molecular Mechanism Underlying Par 1 Gene Over-expression Insupporting

confidence: 72%

PAR₁ plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

et al. 2011

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“…Additionally, reduced nuclear AP-2 expression independently predicted elevated risk of recurrent disease in breast (Gee et al, 2000). Moreover, the loss of AP-2 expression seems to be associated with malignant transformation and tumor progression in malignant melanoma Gee et al, 2000;Bar-Eli, 2001;Tellez et al, 2003). Decreased AP-2 expression is associated with elevated risk of subsequent metastatic behavior in stage I cutaneous malignant melanoma (Karjalainen et al, 1998;Karjalainen et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

AP-2α and AP-2γ are transcriptional targets of p53 in human breast carcinoma cells

Watts

Oshiro

et al. 2006

Oncogene

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Activating enhancer-binding protein 2a (AP-2a) and activating enhancer-binding protein 2c (AP-2c) are transcription factors that bind GC-rich consensus sequences and regulate the expression of many downstream genes. AP-2a and AP-2c interact with p53 both physically and functionally. Expression microarray results in human breast carcinoma cells with forced p53 expression revealed AP-2c as a putative transcriptional target of p53. To confirm and extend these findings we measured the effects of forced p53 expression in human breast carcinoma cells by real-time reverse transcription-PCR, Western blotting, electrophoretic gel mobility shift assays, promoter reporter, chromatin immunoprecipitation and chromatin accessibility assays. Wild-type p53 expression rapidly induced not only AP-2c but also AP-2a mRNA. The subsequent increase in these proteins led to increased AP-2 DNAbinding and transactivating activity. Candidate p53-binding sites were identified in the AP-2a and AP-2c promoters. p53 binding to these cis-elements in vivo was also observed, together with a relaxation of chromatin structure in these regions. Finally, expression of either AP-2a or c inhibited growth of human breast carcinoma cells in vitro. Taken together, our findings indicate that these AP-2 genes are targets for transcriptional activation by p53 and suggest that AP-2 proteins may mediate some of the downstream effects of p53 expression such as inhibition of proliferation.

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“…The reciprocal regulation of transcription of the PAR1 gene by AP2 and Sp1 was also reported in melanoma cells. 90,91 Sp1 positively regulates the transcription of PAR1, whereas AP2 negatively regulates it. 90 In addition, the loss of AP2 expression was found to be correlated to the over-expression of PAR1 and metastatic activity of the melanoma cells.…”

Section: Regulation Of the Expression Of Pars In Vascular Lesionsmentioning

confidence: 99%

“…90 In addition, the loss of AP2 expression was found to be correlated to the over-expression of PAR1 and metastatic activity of the melanoma cells. 91 Recently, Kruppel-like transcription factor 2 (KLF2) was identified as a novel regulator of PAR1 expression in endothelial cells. 92 Forced expression of KLF2 suppressed the transcription of PAR1, thereby inhibiting the thrombin-induced accumulation of nuclear factor B.…”

Section: Regulation Of the Expression Of Pars In Vascular Lesionsmentioning

confidence: 99%

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

Hirano

2007

ATVB

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Abstract-Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors, thus mediating the cellular effects of proteinases. In the vascular system, thrombin and other proteinases in the coagulation-fibrinolysis system are considered to be the physiologically relevant agonists, whereas PARs are among the most important mechanisms mediating the interaction between the coagulation-fibrinolysis system and the vascular wall. Under physiological conditions, PARs are mainly expressed in endothelial cells, and participate in the regulation of vascular tone, mostly by inducing endothelium-dependent relaxation. PARs in endothelial cells are also suggested to contribute to a proinflammatory phenotypic conversion and an increase in the permeability of vascular lesions. In smooth muscle cells, PARs mediate contraction, migration, proliferation, hypertrophy, and production of the extracellular matrix, thereby contributing to the development of vascular lesions and the pathophysiology of such vascular diseases as atherosclerosis. However, the expression of PARs in the smooth muscle of normal arteries is limited. The upregulation of PARs in the smooth muscle is thus considered to be a key step for PARs to participate in the pathogenesis of vascular lesions. Elucidating the molecular mechanism regulating the PARs expression is therefore important to develop new strategies for the prevention and treatment of vascular diseases. (Arterioscler Thromb Vasc Biol. 2007;27:27-36.)

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Loss of Activator Protein-2α Results in Overexpression of Protease-activated Receptor-1 and Correlates with the Malignant Phenotype of Human Melanoma

Cited by 105 publications

References 50 publications

PAR₁ plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

PAR₁ plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

AP-2α and AP-2γ are transcriptional targets of p53 in human breast carcinoma cells

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

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Loss of Activator Protein-2α Results in Overexpression of Protease-activated Receptor-1 and Correlates with the Malignant Phenotype of Human Melanoma

Cited by 105 publications

References 50 publications

PAR1 plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

PAR1 plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

AP-2α and AP-2γ are transcriptional targets of p53 in human breast carcinoma cells

The Roles of Proteinase-Activated Receptors in the Vascular Physiology and Pathophysiology

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PAR₁ plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway

PAR₁ plays a role in epithelial malignancies: Transcriptional regulation and novel signaling pathway