Decreased Expression of Early Growth Response-1 and Its Role in Uterine Leiomyoma Growth

Shozu, Makio; Murakami, Kazuhiko; Segawa, Tomoya; Kasai, Tokuzo; Ishikawa, Hiroshi; Shinohara, Kazunori; Okada, Masahiko; Inoue, Masakí

doi:10.1158/0008-5472.can-03-0560

Cited by 18 publications

(14 citation statements)

References 59 publications

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“…Interestingly, a similar pattern of downregulation of immediate-early SRF targets was also verified in FH-deficient leiomyomas as well as in sporadic leiomyomas. Decreased expression levels of FOS and JUNB in leiomyomas were previously reported (Hoffman et al, 2004;Shozu et al, 2004;Arslan et al, 2005). Although it remains unclear whether or how SRF Ser-103 phosphorylation contributes to activation of SRF target genes, our data strongly suggest that FH-induced alterations in signaling result in reduced FOS-JUNB network expression.…”

Section: Srf-fos-junb Pathway In Myomas N Raimundo Et Alsupporting

confidence: 77%

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

et al. 2009

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Defects of metabolic enzymes result in a variety of manifestations not logically explained by the primary metabolic function. Dominant defects of fumarate hydratase (FH) result in predisposition to cutaneous and uterine leiomyomas, and renal cell cancer. FH is a metabolic enzyme of the tricarboxylic acid cycle, and its tumorsuppressor mechanism is not fully understood. We compared the consequences of FH deficiency and respiratory chain (RC) deficiency using global expression pattern of diploid primary fibroblasts. This approach utilized the information that RC defects do not seem to predispose to tumorigenesis, and the aim was to identify FH-specific signaling effects that might have relevance to tumor formation. These results were then compared to global expression patterns of FH-deficient and sporadic uterine leiomyoma data sets. We show here that FH-deficient fibroblasts share a common transcriptional fingerprint with FH-deficient and sporadic leiomyomas, highlighting the downregulation of serum response factor (SRF)-regulated transcripts, particularly the FOS-JUNB pathway. We confirmed the downregulation of this pathway at transcriptional and protein level. SRF has a fundamental function in the differentiation of smooth muscle progenitor cells, and its downregulation both in diploid FH-deficient primary fibroblasts and in leiomyomas suggests an early function in the mechanism of uterine leiomyoma formation in FH deficiency. Concordantly, the phosphorylated form of SRF, known to activate transcription, is undetectable in leiomyomas whereas clearly detected in several nuclei in the differentiated myometrium. A similar transcriptional SRFpathway fingerprint in FH-deficient and sporadic leiomyomas emphasizes the potential importance of this pathway in primary events leading to leiomyomatosis.

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Section: Srf-fos-junb Pathway In Myomas N Raimundo Et Alsupporting

confidence: 77%

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

et al. 2009

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“…Since the discovery of siRNAs as the key mediator of RNA-induced gene silencing, RNAi has rapidly evolved to become a tool for gene regulation in mammals (26) and has been applied since then to inhibit the expression of a wide variety of target genes. One of them, the Egr-1 gene expressing a transcription factor with important functions in the regulation of growth and differentiation, is involved in the transformed phenotype of several cancer types (34,(39)(40)(41)(42)(43)(44)(45).…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported that Egr-1 can suppress human tumor cell growth and growing evidence suggests that Egr-1 functions as a tumor suppressor gene (37). The role of Egr-1 has been demonstrated in several kind of tumor cells, including human fibrosarcoma, glioblastoma and breast cancer cell lines (37,38), glioblastoma (39), neuroblastoma (10), hepatoma (40), esophageal cancer (41) and leiomyoma (42). In addition, Egr-1 can regulate the coordinated expression of a set of genes, including PTEN ( One day after plating, the cells were transfected with lipofectamine plus siRNA-Egr-1 or scrambled siRNA for 5 h, after which the medium was replaced with fresh medium containing 1 μM or 5 μM Cpt.…”

Section: Discussionmentioning

confidence: 99%

“…siRNA against Egr-1 mRNA prevents the expression of Egr-1 through promoting the degradation of the Egr-1 mRNA while camptothecins have antitumor activity based on their binding to and inhibition of topoisomerase I, a nuclear enzyme which reduces torsional stress during DNA replication and which has an important role in DNA replication. These events could lead to consequent activation of Egr-1 target genes, such as PTEN, TGF-ß1, p53, and fibronectin, which serve to maintain normal growth regulation (37)(38)(39)(40)(41)(42)(43)(44). We found that the protein level of the endogenous Egr-1 was decreased in breast carcinoma cells by the expression of siRNA against the Egr-1 transcription product, which resulted in the suppression of the mRNA-Egr-1 proteins and consequently decreased the activity of Egr-1 in the cells.…”

Section: Discussionmentioning

confidence: 99%

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The effect of siRNA-Egr-1 and camptothecin on growth and chemosensitivity of breast cancer cell lines

Parra

Ferreira²

2010

Oncol Rep

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Abstract.We have examined the effects of a siRNA targeting the Egr-1, alone or in combination with the breast cancer therapeutic camptothecin (Cpt), in suppressing breast cancer cell survival and anchorage-independent growth in the breast cancer cell lines SK-BR3 and MCF-7. In mammary and lung tumors, as well as most normal tissues, Egr-1 expression is low, suggesting a possible relation between the low levels of Egr-1 and the development of mammary neoplasias. However, analyses of the expression of Egr-1 in breast carcinoma cells, SK-BR3 and MCF-7 demonstrated a relatively high expression of the endogenous Egr-1 in these cells. To investigate the effect of the blocking of the endogenous Egr-1 in breast cancer cells, we used small interfering RNA (siRNA) against Egr-1 alone or in combination with Cpt, and expected that the cell sensitivity to chemotherapeutic drug would increase, when blocked with the Egr-1 gene and treated with Cpt. Thus, we performed in vitro experiment to clarify the effect of Egr-1 on tumor cell lines growth. We made control and siRNA-Egr-1 using vector plasmids and then transfected SK-BR3 and MCF-7 cells. After treating the cells with siRNA-Egr-1, the cell lines were assayed with Cpt to confirm the effect of Egr-1 siRNA using the cell expression of mRNA and protein, proliferation assay and anchorage activity with soft agar. Human SK-BR3 and MCF-7 breast carcinoma cell growth and capacity of anchorage transfected with siRNA-Egr-1 or treated with Cpt was slower than that of the control group. This effect was increased when the cells were given simultaneously siRNA and camptothecin. The results strongly suggest that siRNAEgr-1 alone or in combination with camptothecin could be a potent antineoplastic agent in suppressing the growth of breast tumor despite the known role of Egr-1 as a tumorsuppressor in several other types of human cancers.

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“…Cells were treated as described for panels A and B and then subjected to an assay to detect expression of Egr-1 and the internal control GAPDH glyc(glyceraldehyde-3-phosphate dehydrogenase). The details of the primers and PCR conditions used were described previously (47). (D) EBV-negative B-lymphoid cell lines BJAB and Akata were transfected with the vector plasmid (V) or the Zta-expressing plasmid (Z) by electroporation following our previously described protocol (11).…”

Section: Fig 2 Zta Induces Egr-1 Expression (A) Ebv-negative Npc-tmentioning

confidence: 99%

Induction of the Early Growth Response 1 Gene by Epstein-Barr Virus Lytic Transactivator Zta

Chang

Lee

Chen

et al. 2006

J Virol

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Early growth response 1 (Egr-1) is a cellular transcription factor involved in diverse biologic functions. Egr-1 has been associated with Epstein-Barr virus (EBV) infection, but it is still unknown whether any EBV protein regulates Egr-1 expression. In this study, we first showed that EBV reactivation is involved in upregulation of Egr-1 and that Egr-1 can be induced by Zta, an EBV lytic transactivator. Zta not only binds to the Egr-1 promoter but also activates the ERK signaling pathway to trigger binding of Elk-1 to the Egr-1 promoter. In addition, knockdown of Egr-1 significantly reduces the spontaneous expression of Zta and Rta in EBV-infected 293 cells, suggesting that a positive-feedback network involving Egr-1 is required for EBV reactivation. This study also implies that Zta has the potential to affect expression of certain genes through Egr-1.Early growth response 1 (Egr-1), also designated zif268, NGFI-A, and Krox24, is a cellular transcription factor belonging to a family of zinc finger DNA-binding proteins (49). According to its diverse target genes, Egr-1 has been associated with a broad range of biologic functions such as cell proliferation (3, 4, 41), apoptosis (39,51,54), and differentiation (28, 50) in a cell-type-dependent manner. Encoded by an immediate-early gene, Egr-1 can be rapidly induced by many stimuli, including growth factors, cytokines, and various stresses (6,31,44,46). Most of the stimuli trigger cellular signaling converged to mitogen-activated protein kinase (MAPK) pathways, which lead to phosphorylation and activation of a ternary complex factor, Elk-1 (26, 31, 46). Activated Elk-1 interacts with the serum response factor (SRF) to form a ternary complex that binds to a DNA element composed of a core serum response element (SRE) and the adjacent Ets motif (25, 52). There are five such binding sites for the ternary complex in the promoter of the Egr-1-encoding gene, and activation of signal transduction from MAPKs to the ternary complex is essential for Egr-1 expression induced by various stimuli (26,31,45,46).Several clues indicate that Egr-1 is also linked to infection with Epstein-Barr virus (EBV), a human gammaherpesvirus closely associated with several lymphoid and epithelial malignancies (43). First, Egr-1 is upregulated when EBV interacts with B lymphocytes at the initial infection stage, and constitutive expression of Egr-1 correlates with certain types of EBV latency in B-lymphoid cell lines (5). Notably, Egr-1 has also been associated with the lytic state of EBV infection (56). EBV reactivation into the lytic cycle is initiated from activation of two immediate-early viral promoters, Zp and Rp, which are driven to express the BZLF1 (Zta) and BRLF1 (Rta) proteins, respectively (22). Both Zta and Rta are key lytic transactivators which autostimulate their own expression, reciprocally induce each other, and cooperatively direct the downstream expression cascade of EBV lytic genes (18,20,42,48). A previous study showed that Egr-1 can activate Rp and identified two Egr-1-bindi...

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Decreased Expression of Early Growth Response-1 and Its Role in Uterine Leiomyoma Growth

Cited by 18 publications

References 59 publications

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

The effect of siRNA-Egr-1 and camptothecin on growth and chemosensitivity of breast cancer cell lines

Induction of the Early Growth Response 1 Gene by Epstein-Barr Virus Lytic Transactivator Zta

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