Protein kinase C-independent stimulation of activator protein-1 and c-Jun N-terminal kinase activity in human endometrial cancer cells by the LHRH agonist triptorelin

Gründker, Carsten; Schlotawa, Lars; Viereck, Volker; Emons, Günter

doi:10.1530/eje.0.1450651

Cited by 39 publications

(22 citation statements)

References 49 publications

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“…AP1 motifs have been shown to be a converging site for several signal transduction pathways including ERK/MAP kinase, protein kinase C, and c-Jun N-terminal kinase pathways (22)(23)(24). In this study, we used TPA as a tool to explore the regulation of BCSG1 expression in breast cancer cells and we demonstrate that BCSG1 transcription was activated by TPA.…”

Section: Discussionmentioning

confidence: 91%

Blockade of AP1 Transactivation Abrogates the Abnormal Expression of Breast Cancer-specific Gene 1 in Breast Cancer Cells

Lü

Zhang

Gupta

et al. 2002

Journal of Biological Chemistry

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Breast cancer-specific gene 1 (BCSG1) is not expressed in normal breast tissue but is highly expressed in the vast majority of invasive and metastatic breast carcinomas. When over-expressed, BCSG1 significantly stimulates the proliferation and invasion of breast cancer cells. The accumulated evidence suggests that the aberrant expression of BCSG1 in breast carcinomas is caused by transcriptional activation of the BCSG1 gene. However, the transcription factors that activate BCSG1 transcription have not been identified. In this study, we extensively investigated the role of AP1 in BCSG1 expression in breast cancer cells. We demonstrate that there are two closely located AP1 binding sites residing in the first intron of the BCSG1 gene. Mutation of either AP1 motif on the BCSG1 promoter constructs markedly reduces the promoter activity. We further show that 12-O-tetradecanoylphorbol-13-acetate (TPA) increases BCSG1 mRNA expression and up-regulates BCSG1 promoter activity through the intronic AP1 sites. The effect of TPA on BCSG1 transcription is also demonstrated under in vivo conditions in intact cells by using chromatin immunoprecipitation assays that show the TPA-induced binding of c-Jun to the chromatin region encompassing the intronic AP1 sites. Finally, to examine the direct effect of AP1 transactivation on BCSG1 expression, we established stable cell lines of T47D that express the dominant negative mutant of c-Jun, TAM67. RT-PCR and Western blot analyses demonstrated that levels of BCSG1 mRNA and protein in TAM67 transfectants were drastically reduced as compared with mocktransfected cells. Furthermore, inhibition of BCSG1 expression by blocking AP1 transactivation produced a similar repressive effect on cell growth as that by expressing BCSG1 antisense mRNA. We show that the anchorage-independent growth of T47D cells expressing either TAM67 or BCSG1 antisense mRNA is significantly inhibited. Taken together, we provide strong evidence that AP1 plays an overriding role in the transcription of the BCSG1 gene and that blockade of AP1 transactivation down-regulates BCSG1 expression and suppresses tumor phenotype.Previous studies conducted by differential DNA sequencing and in situ hybridization have identified BCSG1 1 (1), also referred to as synuclein ␥ (2) or persyn (3), as a breast cancerspecific gene because of its distinct expression pattern in breast tissues. BCSG1 is not expressed in normal breast tissue or tissues with benign breast diseases but is highly expressed in the vast majority of stage III/IV breast carcinomas (1, 4). BCSG1 expression in advanced breast carcinomas is not merely adventitious but plays a positive role in the process of invasion and metastasis. It has been demonstrated that exogenous expression of BCSG1 in breast cancer cells leads to a significant increase in cell motility and cell proliferation in cell culture (5, 6), as well as a profound augmentation of metastasis in nude mice (5). Thus far, BCSG1 gene mutations or amplifications have not been found by examination of breast carc...

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Section: Discussionmentioning

confidence: 91%

Blockade of AP1 Transactivation Abrogates the Abnormal Expression of Breast Cancer-specific Gene 1 in Breast Cancer Cells

Lü

Zhang

Gupta

et al. 2002

Journal of Biological Chemistry

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“…In addition, triptorelin activates c-Jun N-terminal kinase (JNK), which is known to activate AP-1 (102). In earlier investigations, we have shown that triptorelin does not activate PLC and PKC in endometrial and ovarian cancer cells (76).…”

Section: Additional Signaling Mechanismsmentioning

confidence: 98%

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Gründker

Gunthert

Westphalen

et al. 2002

European Journal of Endocrinology

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155

139

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The expression of GnRH and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the breast, ovary and endometrium. Dose-dependent antiproliferative effects of GnRH agonists in cell lines derived from these cancers have been observed by various investigators. GnRH antagonists also have marked antiproliferative activity in most breast, ovarian and endometrial cancer cell lines tested, indicating that the dichotomy of GnRH agonists and antagonists might not apply to the GnRH system in cancer cells. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in cancer cells. Rather, the GnRH receptor interacts with the mitogenic signal transduction of growth factor receptors and related oncogene products associated with tyrosine kinase activity, via activation of a phosphotyrosine phosphatase, resulting in downregulation of cancer cell proliferation. In addition, GnRH activates nuclear factor kB and protects the cancer cells from apoptosis. Furthermore, GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (AP-1) pathway independent of the known AP-1 activators, protein kinase or mitogen activated protein kinase.

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“…However, there is little evidence for PLC activation by endogenous extrapituitary LHRH-R-I (44,48). Instead, G i -mediated activation of protein phosphatase and inhibition of MAP kinase activity may be the basis of some of the antiproliferative effects mediated by LHRH-R-I (44,46,52,53). Investigation of the expression of extrapituitary LHRH-R-I revealed major functional differences between LHRH-R-I in human pituitary and extrapituitary sites, in spite of the expression of identical receptor transcripts (19).…”

Section: Discussionmentioning

confidence: 99%

Expression of mRNA for human type-I LHRH receptor transcript forms in human benign prostatic hyperplasia

et al. 2009

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Abstract. The presence of four different isoforms of luteinizing hormone-releasing hormones (LHRH) and one LHRH receptor (LHRH-R) has been reported in vertebrates. In the human genome only LHRH-I and LHRH-II genes have been identified. The human LHRH-I gene is composed of four exons separated by three introns. Three LHRH receptor or receptor-like genes have been demonstrated. The wellestablished type-I LHRH receptor (LHRH-R-I) gene is composed of three exons separated by two introns. In this study we investigated the expression of transcript forms of LHRH-R-I in human benign prostatic hyperplasia (BPH) with reverse transcriptase-polymerase chain reaction (RT-PCR) using gene specific primers. Thirty-five human BPH specimens were obtained at surgery. Normal human pituitaries collected at autopsy served as control. RNA extraction and RT-PCR with gene-specific primers for LHRH-R-I forward (F1)/reverse (R1), LHRH-R-I F2/R3, LHRH-R-I F1'/R2' were carried out to determine the mRNA expression for LHRH-R-I transcript forms. The expected PCR products amplified with gene specific primers were LHRH-R-I F1/R1 with 319 bp, LHRH-R-I F2/R3 with 309 bp and LHRH-R-I F1'/R2' with 219 bp. PCR products for LHRH-R-I F1/R1 were detected in 21 (60%) and for LHRH-R-I F2/R3 in 5 of 35 (14%) BPH samples. No PCR products for LHRH-R-I F1'/R2' were found. In conclusion, we detected mRNA for LHRH-R-I in human BPH specimens. Our results suggest that LHRH-R-I gene may have more than two splice variants or uncharacterised transcript forms of LHRH-R-I. Our findings support the merit of further investigation of the expression of LHRH-R-I and its transcript forms in human BPH.

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Protein kinase C-independent stimulation of activator protein-1 and c-Jun N-terminal kinase activity in human endometrial cancer cells by the LHRH agonist triptorelin

Cited by 39 publications

References 49 publications

Blockade of AP1 Transactivation Abrogates the Abnormal Expression of Breast Cancer-specific Gene 1 in Breast Cancer Cells

Blockade of AP1 Transactivation Abrogates the Abnormal Expression of Breast Cancer-specific Gene 1 in Breast Cancer Cells

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Expression of mRNA for human type-I LHRH receptor transcript forms in human benign prostatic hyperplasia

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