Transcription Factor AP-2α Is Preferentially Cleaved by Caspase 6 and Degraded by Proteasome during Tumor Necrosis Factor Alpha-Induced Apoptosis in Breast Cancer Cells

Nyormoi, Okot; Wang, Zhi; Doan, Dao; Ruiz, Maribelís; McConkey, David J.; Bar‐Eli, Menashe

doi:10.1128/mcb.21.15.4856-4867.2001

Cited by 53 publications

(29 citation statements)

References 77 publications

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“…Finally, we showed that the interplay among AP-2, HMGA1, and Sp1 had functional sequelae also in MCF-7 cells, a cell line ideally suited for studying the effects of these proteins on transcription because it does not express appreciable levels of either HMGA1 or Sp1 (34,35), whereas AP-2 is constitutively expressed (21). As shown in Fig.…”

Section: Ap-2 and Ir Overexpression Inmentioning

confidence: 88%

“…An involvement of AP-2 family of proteins in the etiology of human breast cancer has been shown in previous studies, in which a significant up-regulation of AP-2a in breast cancer specimens has been observed (21). In addition, AP-2 genes are expressed in many human breast cancer cell lines, and AP-2 consensus binding sites can be detected in both c-erbB-2 and estrogen receptor promoters, whose activity is increased in breast cancers (22,23).…”

Section: Introductionmentioning

confidence: 99%

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Activator Protein-2 Overexpression Accounts for Increased Insulin Receptor Expression in Human Breast Cancer

et al. 2006

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Various studies have shown that the insulin receptor (IR) is increased in most human breast cancers, and both liganddependent malignant transformation and increased cell growth occur in cultured breast cells overexpressing the IR. However, although numerous in vivo and in vitro observations have indicated an important contributory role for the IR in breast cancer cell biology, the molecular mechanisms accounting for increased IR expression in breast tumors have not previously been elucidated. Herein, we did immunoblot analyses of nuclear protein from cultured breast cancer cells and normal and tumoral tissues from breast cancer patients combined with promoter studies by using a series of human wild-type and mutant IR promoter constructs. We provide evidence that IR overexpression in breast cancer is dependent on the assembly of a transcriptionally active multiprotein-DNA complex, which includes the high-mobility group A1 (HMGA1) protein, the developmentally regulated activator protein-2 (AP-2) transcription factor and the ubiquitously expressed transcription factor Sp1. In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression. However, AP-2 DNAbinding activity was undetectable with the IR gene promoter, suggesting that transactivation of this gene by AP-2 might occur indirectly through physical and functional cooperation with HMGA1 and Sp1. Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis. (Cancer Res 2006; 66(10): 5085-93)

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Section: Ap-2 and Ir Overexpression Inmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Activator Protein-2 Overexpression Accounts for Increased Insulin Receptor Expression in Human Breast Cancer

et al. 2006

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“…In the presence of 5a, TNFa-induced cell death was accelerated and reached a maximum level within 12-20 h instead of 48 h, as we previously demonstrated. 32 It should be noted that adding TNFa before 5a had the same effect as adding TNFa alone.…”

Section: Effect Of Compound 5a On Tnfa-induced Apoptosismentioning

confidence: 99%

“…32 Briefly, cells were treated with the appropriate agents as described elsewhere in this paper. At least 5 Â 10 5 cells were removed from the plate, pelleted at 900 Â g in a swing bucket centrifuge, washed once with PBS, and resuspended in 0.75 ml of a 50 mg/ml solution of propidium iodide, comprising 3 mM sodium citrate and 0.1% Triton X-100.…”

Section: Flow Cytometrymentioning

confidence: 99%

An MMP-2/MMP-9 inhibitor, 5a, enhances apoptosis induced by ligands of the TNF receptor superfamily in cancer cells

2003

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Several studies have shown that matrix metalloproteases (MMPs) promote tumor growth, invasion, and metastasis. Consequently, MMP inhibitors have been developed as a new class of anticancer drugs, many of which are in clinical trials. The exact mechanism of the antineoplastic activity of MMP antagonists is unknown. To investigate the mechanism, we hypothesized that MMP inhibitors enhance the actions of apoptosis-inducing agents. To test this hypothesis, we treated breast, melanoma, leukemia, osteosarcoma, and normal breast epithelial cells with (2R)-2-[(4-biphenylsulfonyl)amino]-3-phenylproprionic acid (compound 5a), an organic inhibitor of MMP-2/MMP-9, alone or in combination with TNFa or other apoptotic agents. FACS analysis showed that 5a interacted synergistically with ligands of the TNF receptor superfamily, including TNFa and TNF receptor-like apoptosisinducing ligand (TRAIL), and with a Fas-cross-linking antibody (CH11), UV, paclitaxel, thapsigargin, and staurosporin, to induce apoptosis in a cell-type-specific manner. Other MMP inhibitors did not synergize with TNFa. Compound 5a did not act directly on the mitochondrion or via changes in protein synthesis. Instead, the mechanism requires ligandreceptor interaction and caspase 8 activation. Investigation of the effect of 5a on tumor growth in vivo revealed that continuous treatment of subcutaneous melanoma with a combination of 5a plus TRAIL reduced tumor growth and angiogenesis in nude mice. Our data demonstrate that 5a possesses a novel proapoptotic function, thus providing an alternative mechanism for its antineoplastic action. These observations have important implications for combination cancer therapy.

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“…The loss of AP-2 results in the suppression of endogenous AP-2 transactivator function that may inhibit melanoma cells to respond to growth and differentiation regulatory signals (10,11). Furthermore, inactivation of AP-2 by means of dominant-negative AP-2 gene resulted in an increase of tumorigenicity and metastasis potential in primary cutaneous melanoma cells (6).…”

Section: Introductionmentioning

confidence: 99%

Automated Quantitative Analysis of Activator Protein-2α Subcellular Expression in Melanoma Tissue Microarrays Correlates with Survival Prediction

Berger

Davis

Tellez³

et al. 2005

Cancer Research

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The activator protein-2A (AP-2) transcription factor plays a key role in regulating expression of genes involved in tumor growth and metastasis of human melanoma. We sought to assess the prognostic significance of AP-2 expression and its role in the transition of nevi to metastatic melanoma. Two cohorts were analyzed. One was a ''progression'' microarray containing melanoma specimens from M.D. Anderson Cancer Center representing 84 cases and the other was a retrospective cohort from Yale University representing 214 primary melanomas and 293 metastases. Analysis of total AP-2 expression using two quantitative systems [automated quantitative analysis (AQUA) and laser scanning cytometry (LSC)] revealed no correlation with diagnosis group. LSC analysis of the M.D. Anderson Cancer Center array showed that the number of cells expressing nuclear AP-2 was highest in the benign nevi group (11.85%) and significantly decreased in each phase of melanoma progression to 0.39% in the metastatic group. Both LSC and AQUA showed decreased nuclear AP-2 levels and increased cytoplasmic AP-2 that is directly proportional to progression. Neither nuclear nor cytoplasmic expression levels correlated with outcome. Intriguingly, the ratio of cytoplasmic to nuclear AP-2 predicted outcome in the entire population and in the primary tumors alone, demonstrating the power of the ratio to normalize for variations. Furthermore, the AP-2 ratio directly correlated with other clinicopathologic factors, including Breslow depth (R = 0.334, P < 0.001). We show that a high level of AP-2 expression in the cytoplasm relative to the nucleus correlates with poor prognosis and the loss of nuclear AP-2 expression is associated with malignant transformation and progression of melanoma. (Cancer Res 2005; 65(23): 11185-92)

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Transcription Factor AP-2α Is Preferentially Cleaved by Caspase 6 and Degraded by Proteasome during Tumor Necrosis Factor Alpha-Induced Apoptosis in Breast Cancer Cells

Cited by 53 publications

References 77 publications

Activator Protein-2 Overexpression Accounts for Increased Insulin Receptor Expression in Human Breast Cancer

Activator Protein-2 Overexpression Accounts for Increased Insulin Receptor Expression in Human Breast Cancer

An MMP-2/MMP-9 inhibitor, 5a, enhances apoptosis induced by ligands of the TNF receptor superfamily in cancer cells

Automated Quantitative Analysis of Activator Protein-2α Subcellular Expression in Melanoma Tissue Microarrays Correlates with Survival Prediction

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