The Role of the AP-1 Transcription Factors c-Fos, FosB, Fra-1 and Fra-2 in the Invasion Process of Mammary Carcinomas

Milde‐Langosch, Karin; Röder, Heike; Andritzky, Birte; Aslan, Bahriye; Hemminger, Gabriele; Brinkmann, Anja; Bamberger, Christoph M.; Löning, Thomas; Bamberger, Ana‐Maria

doi:10.1023/b:brea.0000032982.49024.71

Cited by 113 publications

(99 citation statements)

References 18 publications

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“…These results come in line and extend the most recent notion that, in mouse fibroblasts, HARP expression is up-regulated by Jun (31). Interestingly, HARP expression is also regulated by Fra-1, a member of the AP-1 family that seems to regulate genes that are required for migration/invasion (21,32,33). HARP has been implicated in migration of several types of cells (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Peroxide Stimulates Proliferation and Migration of Human Prostate Cancer Cells through Activation of Activator Protein-1 and Up-regulation of the Heparin Affin Regulatory Peptide Gene

Polytarchou

Hatziapostolou

Papadimitriou

2005

Journal of Biological Chemistry

131

109

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It is becoming increasingly recognized that hydrogen peroxide (HP) plays a role in cell proliferation and migration. In the present study we found that exogenous HP significantly induced human prostate cancer LNCaP cell proliferation and migration. Heparin affin regulatory peptide (HARP) seems to be involved in the stimulatory effect of HP, because the latter had no effect on stably transfected LNCaP cells that did not express HARP. Moreover, HP significantly increased HARP mRNA and protein amounts in a concentration-and time-dependent manner. Curcumin and activator protein-1 (AP-1) decoy oligonucleotides abrogated both HPinduced HARP expression and LNCaP cell proliferation and migration. HP increased luciferase activity of the 5-flanking region of the HARP gene introduced in a reporter gene vector, an effect that was abolished when even one of the two putative AP-1 binding sites of the HARP promoter was mutated. The effect of HP seems to be due to the binding of Fra-1, JunD, and phospho-c-Jun to the HARP promoter. These results support the notion that HARP is important for human prostate cancer cell proliferation and migration, establish the role of AP-1 in the up-regulation of HARP expression by low concentrations of HP, and characterize the AP-1 dimers involved.A growing body of evidence correlates the production of reactive oxygen species with many aspects of cellular functions (1). Reactive oxygen species include the superoxide, hydrogen peroxide (HP), 2 and the hydroxyl radical. Of these, HP has the chemical stability required to establish significant steady-state concentrations in vivo (2, 3) and is small and uncharged, properties that allow it to freely diffuse across plasma membranes and make it an ideal candidate for a signaling molecule (4). Small quantities of HP are produced by all types of cells, and several signal transduction pathways in mammalian cells have been reported to be activated by HP, such as tyrosine kinases, mitogen-activated protein kinases, protein kinase C, the epidermal growth factor receptor, protein phosphatases, potassium channels, and the transcription factors activator protein-1 (AP-1), and nuclear factor B (reviewed in ref. 1).Heparin affin regulatory peptide (HARP), also called pleiotrophin or heparin-binding growth-associated molecule, is an 18-kDa secreted growth factor that displays high affinity for heparin. A growing body of evidence indicates that HARP is involved in cell proliferation, migration, and differentiation and plays a significant role in several cellular processes (5, 6). HARP seems to play a major role in physiological as well as tumor angiogenesis and is detected in various carcinomas, such as human breast and prostate cancer, neuroblastomas, gliomas, benign meningiomas, and small cell lung cancer and mammary tumors, exhibiting a proto-oncogene function (5-8).HARP is highly conserved among human, rat, bovine, and mouse species, and its gene is expressed in a highly restricted temporal and spatial pattern during development, suggesting that HARP may be an ...

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Section: Discussionmentioning

confidence: 99%

Hydrogen Peroxide Stimulates Proliferation and Migration of Human Prostate Cancer Cells through Activation of Activator Protein-1 and Up-regulation of the Heparin Affin Regulatory Peptide Gene

Polytarchou

Hatziapostolou

Papadimitriou

2005

Journal of Biological Chemistry

131

109

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“…Western blot conditions for all AP-1 proteins have been described in our previous publication (Bamberger et al, 1999). Fra-1 and Fra-2 are characterised by two or more bands in Western blots representing different phosphorylation states, which were evaluated separately as described (Milde-Langosch et al, 2004). For all AP-1 proteins, the samples were divided into two groups of similar size (weak and strong immunoreactivity) according to their expression levels for statistical correlations.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…The results were statistically correlated with clinical and histological data, the steroid hormone receptor status as well as recurrence-free and overall survival. Since 75 cases of our cohort had been characterised before with respect to the expression of the AP-1 proteins, several cell-cycle regulatory proteins (cyclin D1 and E, Rb, Rb2, p16, p21, p27), Ki67 and HER2/neu, the matrix metalloproteinases MMP1 and MMP9 and members of the uPA -PAI-1 system (Bamberger et al, 1999;MildeLangosch et al, 2000;Milde-Langosch et al, 2004), we analysed possible associations of these factors with ERK1/2 or p-ERK1/2 expression.…”

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confidence: 99%

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

et al. 2005

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Extracellular-regulated kinases (ERK1, ERK2) play important roles in the malignant behaviour of breast cancer cells in vitro. In our present study, 148 clinical breast cancer samples (120 cases with follow-up data) were studied for the expression of ERK1, ERK2 and their phosphorylated forms p-ERK1 and p-ERK2 by immunoblotting, and p-ERK1/2 expression in corresponding paraffin sections was analysed by immunohistochemistry. The results were correlated with established clinical and histological prognostic parameters, follow-up data and expression of seven cell-cycle regulatory proteins as well as MMP1, MMP9, PAI-1 and AP-1 transcription factors, which had been analysed before. High p-ERK1 expression as determined by immunoblots correlated significantly with a low frequency of recurrences and infrequent fatal outcome (P ¼ 0.007 and 0.008) and was an independent indicator of long relapse-free and overall survival in multivariate analysis. By immunohistochemistry, strong p-ERK staining in tumour cells was associated with early stages (P ¼ 0.020), negative nodal status (P ¼ 0.003) and long recurrence-free survival (P ¼ 0.017). In contrast, expression of the unphosphorylated kinases ERK1 and ERK2 was not associated with clinical and histological prognostic parameters, except a positive correlation with oestrogen receptor status. Comparison with the expression of formerly analysed cell-cycle-and invasion-associated proteins corroborates our conclusion that activation of ERK1 and ERK2 is not associated with enhanced proliferation and invasion of mammary carcinomas. Growth factors or cytokines exert positive and negative effects on cell proliferation and differentiation. After binding to their membrane receptors, the message is relayed to the nucleus by a complex system of intracellular signalling pathways. The majority of signalling molecules involved in these pathways are kinases, which are themselves activated by phosphorylation and repressed by their specific phosphatases. The mitogen-activated protein kinase (MAPK) signalling pathway includes a cascade of four groups of kinases (MAPKKKKs, MAPKKKs, MAPKKs and MAPKs). The MAPK kinase kinase kinases of the first level are phosphorylated in response to various extracellular stimuli through interaction with small GTP-binding proteins like Ras, Raf, etc. The activated enzymes then phosphorylate one of 14 kinases of the second level (the MAPKKKs, that is, Raf proteins, MEKK1-4, etc.), which themselves activate one of the MAPK kinases (MEK1 and 2, MKK3 -7) of the third level. Finally, these kinases (MAPKKs) activate MAP kinases, which are then able to phosphorylate transcription factors, which regulate the expression of genes involved in cell proliferation or differentiation. Three different, partly interacting signalling pathways have been identified in mammalian cells, leading to the activation of three types of MAP kinases: the MAP kinase JNK (Jun kinase) phosphorylates c-Jun, JunB, ATF2 and ELK1, etc., P38 activates ATF2, ELK-1 and MAX, whereas ERK1 and ERK2 phosphorylate...

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“…Nevertheless, recent data point to a positive effect of Fra-1, and partly Fra-2, on tumor invasion and progression in many tumor types (110,111). Moreover, a model was proposed in which both Fra-1 and c-Fos act as adaptors for other transcription factors, or as transcriptional repressors rather than transcriptional activators (112).…”

Section: Ap-1 As a Potential Treatment Target In Respiratory Epithelimentioning

confidence: 99%

The Activator Protein-1 Transcription Factor in Respiratory Epithelium Carcinogenesis

Karamouzis

Konstantinopoulos²,

Papavassiliou³

2007

Molecular Cancer Research

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Respiratory epithelium cancers are the leading cause of cancer-related death worldwide. The multistep natural history of carcinogenesis can be considered as a gradual accumulation of genetic and epigenetic aberrations, resulting in the deregulation of cellular homeostasis. Growing evidence suggests that crosstalk between membrane and nuclear receptor signaling pathways along with the activator protein-1 (AP-1) cascade and its cofactor network represent a pivotal molecular circuitry participating directly or indirectly in respiratory epithelium carcinogenesis. The crucial role of AP-1 transcription factor renders it an appealing target of future nuclear-directed anticancer therapeutic and chemoprevention approaches. In the present review, we will summarize the current knowledge regarding the implication of AP-1 proteins in respiratory epithelium carcinogenesis, highlight the ongoing research, and consider the future perspectives of their potential therapeutic interest. (Mol Cancer Res 2007;5(2):109 -20)

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The Role of the AP-1 Transcription Factors c-Fos, FosB, Fra-1 and Fra-2 in the Invasion Process of Mammary Carcinomas

Cited by 113 publications

References 18 publications

Hydrogen Peroxide Stimulates Proliferation and Migration of Human Prostate Cancer Cells through Activation of Activator Protein-1 and Up-regulation of the Heparin Affin Regulatory Peptide Gene

Hydrogen Peroxide Stimulates Proliferation and Migration of Human Prostate Cancer Cells through Activation of Activator Protein-1 and Up-regulation of the Heparin Affin Regulatory Peptide Gene

Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer

The Activator Protein-1 Transcription Factor in Respiratory Epithelium Carcinogenesis

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