Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma.

Karjalainen, Jari; Kellokoski, Jari; Eskelinen, Matti; Alhava, Esko; Kosma, Veli‐Matti

doi:10.1200/jco.1998.16.11.3584

Cited by 100 publications

(107 citation statements)

References 29 publications

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“…Immunohistochemical studies have shown that downregulated cytoplasmic AP-2a expression was consistently seen in high grade and advanced Duke's stage tumors (Ropponen et al, 2001). In addition, low cytoplasmic AP-2a expression was seen in high-grade carcinomas (Ropponen et al, 2001), corroborating previous reports in which low AP-2a expression was associated with higher tumor malignancy and poor survival (Karjalainen et al, 1998;Ropponen et al, 1999;Pellikainen et al, 2003). However, the exact mechanism by which loss of AP-2a contributes to colon cancer progression is yet to be investigated.…”

Section: Introductionsupporting

confidence: 87%

“…Loss of AP-2a expression has been associated with progression of melanoma , prostate cancer (Ruiz et al, 2004) and colorectal cancer (Ropponen et al, 1999(Ropponen et al, , 2001). In addition, immunohistochemical studies of human melanoma, breast and colorectal cancer specimens have revealed that loss of AP-2a coincides with poor prognosis (Karjalainen et al, 1998;Ropponen et al, 1999;Pellikainen et al, 2004). We have demonstrated previously that normal melanocytes and nonmetastatic melanoma cell lines express high levels of AP-2a.…”

Section: Introductionmentioning

confidence: 84%

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Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

et al. 2007

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Activator protein-2 (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells and has been implicated in the acquisition of the metastatic phenotype in several types of cancer. Herein, we examine the role of AP-2a in colon cancer progression. We provide evidence for the lack of AP-2a expression in the late stages of colon cancer cells. Re-expression of the AP-2a gene in the AP-2a-negative SW480 colon cancer cells suppressed their tumorigenicity following orthotopic injection into the cecal wall of nude mice. The inhibition of tumor growth could be attributed to the increased expression of E-cadherin and decreased expression and activity of matrix-metalloproteinase-9 (MMP-9) in the transfected cells, as well as a substantial loss of their in vitro invasive properties. Conversely, targeting constitutive expression of AP-2a in AP-2-positive KM12C colon cancer cells with small interfering RNA resulted in an increase in their invasive potential, downregulation of E-cadherin and increased expression of MMP-9. In SW480 cells, re-expression of AP-2a resulted in a fourfold increase in the activity of E-cadherin promoter, and a 5-14-fold decrease in the activity of MMP-9 promoter, indicating transcriptional regulation of these genes by AP-2a. Chromatin immunoprecipitation assay showed that re-expressed AP-2a directly binds to the promoter of E-cadherin, where it has been previously reported to act as a transcriptional activator. Furthermore, chromatin immunoprecipitation assay revealed AP-2a binding to the MMP-9 promoter, which ensued by decreased binding of transcription factor Sp-1 and changes in the recruitment of transcription factors to a distal AP-1 element, thus, contributing to the overall downregulation of MMP-9 promoter activity. Collectively, our data provide evidence that AP-2a acts as a tumor suppressor gene in colon cancer.

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Section: Introductionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 84%

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

et al. 2007

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“…Moreover, it has been reported that overexpression of AP-2 in highly metastatic melanoma cell lines inhibits their tumor growth and metastatic potential in nude mice ). Finally, a significant negative correlation between AP-2 expression level and elevated risk of subsequent metastatic behavior has been described (Huang et al, 1998;Karjalainen et al, 1998;Baldi et al, 2001a).…”

Section: Genetics Of Cutaneous Melanomamentioning

confidence: 96%

cDNA array technology in melanoma: An overview

Baldi¹,

Santini²,

Luca³

et al. 2003

Journal Cellular Physiology

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Genetic aberrations, mostly resulting in changes in gene expression, are critical events in cancer onset and progression. The advent of the cDNA array technology allows the screening and the efficient measurement of expression of thousands genes simultaneously in a wide spectrum of experimental and clinical models. This genomic scale approach is being currently used to obtain global views of human cancer gene expression and to identify genetic markers that might be important for diagnosis, prognosis, and therapy. This review discusses some recent findings obtained by means of cDNA arrays investigating the human melanoma.

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“…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). Re-expression of AP-2 in the highly metastatic melanoma cells decreased their tumorigenicity and inhibited their metastatic potential in nude mice (Bar-Eli, 2001).…”

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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Downregulation of transcription factor AP-2 predicts poor survival in stage I cutaneous malignant melanoma.

Cited by 100 publications

References 29 publications

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

cDNA array technology in melanoma: An overview

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

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