Cooperation between Fibroblast Growth Factor Receptor-4 and ErbB2 in Regulation of Cyclin D1 Translation

Koziczak, Magdalena; Hynes, Nancy E.

doi:10.1074/jbc.m404252200

Cited by 61 publications

(49 citation statements)

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“…Here, we show that knocking-down 4E-BP1 markedly increases the polysomal association of the cyclin D1 mRNA and eliminates the effect of rapamycin treatment on cyclin D1 levels. However, this differs from the conclusions of a study performed in MDA-MB-453 cells (Koziczak and Hynes, 2004). The elimination of S6K expression by siRNA modestly decreased (20-30%) cyclin D1 expression.…”

Section: Discussioncontrasting

confidence: 98%

“…The control of cyclin D1 mRNA translation is complex, involving both cap-dependent and cap-independent mechanisms (Gera et al, 2004). Previous data suggested roles for S6Ks (Koziczak and Hynes, 2004) and eIF4E/4E-BP1 (Rosenwald et al, 1993;Guan et al, 2007) in the regulation of cyclin D1 expression. Here, we set out to clarify the roles of these mTORC1 targets in controlling cyclin D1 expression.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

2007

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There is currently substantial interest in the regulation of cell function by mammalian target of rapamycin (mTOR), especially effects linked to the rapamycin-sensitive mTOR complex 1 (mTORC1). Rapamycin induces G 1 arrest and blocks proliferation of many tumor cells, suggesting that the inhibition of mTORC1 signaling may be useful in cancer therapy. In MCF7 breast adenocarcinoma cells, rapamycin decreases levels of cyclin D1, without affecting cytoplasmic levels of its mRNA. In some cell-types, rapamycin does not affect cyclin D1 levels, whereas the starvation for leucine (which impairs mTORC1 signaling more profoundly than rapamycin) does. This pattern correlates with the behavior of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1, an mTORC1 target that regulates translation initiation). siRNA-mediated knockdown of 4E-BP1 abrogates the effect of rapamycin on cyclin D1 expression and increases the polysomal association of the cyclin D1 mRNA. Our data identify 4E-BP1 as a key regulator of cyclin D1 expression, indicate that this effect is not mediated through the changes in cytoplasmic levels of cyclin D1 mRNA and suggest that, in some cell types, interfering with the amino acid input to mTORC1, rather than using rapamycin, may inhibit proliferation.

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Section: Discussioncontrasting

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

2007

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“…Cancer cell line assay results suggest that cooperation exists between FGFR and receptors of the EGFR family in oncogenesis ( 20 ). Overexpression and activation of FGFR1 and HER2 have been observed in breast cancer, and the combined inhibition of both receptors led to a stronger antitumor activity compared with each treatment alone in a mouse model ( 93 ). In addition, we described different mechanisms by which FGFR signaling could contribute to resistance to available targeted treatments, such as anti-EGFRs (e.g., vemurafenib and imatinib), and future research must determine the optimal selection of the most appropriate combinations from the pool of new molecularly targeted agents.…”

Section: Combining Fgfr and Other Kinase Inhibitorsmentioning

confidence: 98%

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

et al. 2013

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The fi broblast growth factor/fi broblast growth factor receptor (FGF/FGFR) signaling pathway plays a fundamental role in many physiologic processes, including embryogenesis, adult tissue homeostasis, and wound healing, by orchestrating angiogenesis. Ligand-independent and ligand-dependent activation have been implicated in a broad range of human malignancies and promote cancer progression in tumors driven by FGF/FGFR oncogenic mutations or amplifi cations, tumor neoangiogenesis, and targeted treatment resistance, thereby supporting a strong rationale for anti-FGF/FGFR agent development. Efforts are being pursued to develop selective approaches for use against this pathway by optimizing the management of emerging, classspecifi c toxicity profi les and correctly designing clinical trials to address these different issues.Signifi cance: FGF/FGFR pathway deregulations are increasingly recognized across different human cancers. Understanding the mechanisms at the basis of these alterations and their multiple roles in cancer promotion and drug resistance is a fundamental step for further implementation of targeted therapies and research strategies. Cancer Discov;3(3);

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“…Selective FGFR inhibitor PD blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion; PD was also found to significantly strengthen the effect of cisplatin and increase apoptosis (9). PD weakens the activity of FGFR4 and reduces the phosphorylation FGFR4 in breast cancer and medullary thyroid cancer (10,11). In the thyroid cancer cell lines MRO and ARO with high FGFR4 expression, cell proliferation gradually decreased with increasing PD concentration.…”

Section: Discussionmentioning

confidence: 99%

Combination of the FGFR4 inhibitor PD173074 and 5-fluorouracil reduces proliferation and promotes apoptosis in gastric cancer

Shi

et al. 2013

Oncology Reports

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Abstract. Our previous findings revealed that FGFR4 may be a novel therapeutic target for gastric cancer. The aim of the present study was to explore the effects of a combination of PD173074 (PD) and 5-fluorouracil (5-Fu) on the biological behavior of gastric cancer cell lines and the relevant mechanisms involved. MKN45, a gastric cancer cell line, was treated with each single agent alone or a combination of FGF19, PD and 5-Fu. Then, a series of functional assays were performed using CCK-8 assay and flow cytometry. Western blot analysis was used to determine the expression of signaling pathway and downstream-related molecules in the MKN45 cells following the different treatments. As the concentration of PD and 5-Fu increased, the cell viability gradually decreased; the viability of the combination group was less than the viability following single administration. Western blot analysis showed that FGFR4 expression was weak in the 5-Fu-treated groups when compared with the control. PD markedly increased the apoptosis rate of MKN45 cells when compared to the control; the apoptosis rate in the cells treated with the combination of PD and 5-Fu was higher than that in the cells following single treatment. Furthermore, PD reduced the expression of p-ERK and Bcl-xl and increased caspase-3 expression. Inhibition of the activity of FGFR4 may be the main mechanisms of PD effect while 5-Fu reduced FGFR4 expression. Furthermore, the effects of the combination of 5-Fu and PD in inhibiting proliferation, increasing apoptosis and arresting cell cycle were superior to these effects following the single agent treatments, suggesting that the two drugs applied in combination may contribute to the effective treatment of gastric cancer. IntroductionGastric cancer (GC) is the fourth most common malignant tumor worldwide (1). GC patients in China have an extremely high rate of morbidity and mortality. Patients with earlystage GC account for only 20% of cases in China, which is much less than that in Japan and Korea. Therefore, most GC patients in China are diagnosed with advanced GC and require comprehensive therapy including surgery, radiotherapy and chemotherapy. Currently, there are many neoadjuvant, adjuvant and palliative chemotherapies available for GC patients, such as ECF, DCF, oxaliplatin and 5-fluorouracil (5-Fu). However, the most crucial drug is 5-Fu. Recently, targeted drugs have become an intense field in the research and application of GC treatment. Cetuximab (targeted to EGFR), bevacizumab (targeted to VEGF) and Herceptin (targeted to Her-2) have been applied in clinical trails of gastric cancer. Importantly, in October 2010, the Food and Drug Administration approved the combination of Herceptin and chemotherapy for the treatment of late-stage or metastatic GC patients with positive expression of Her-2.However, to date, no other targeted drugs have achieved a breakthrough in the treatment of GC apart for Herceptin. Although targeted drug treatment is the future direction, exploring new therapeutic targets in GC has beco...

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Cooperation between Fibroblast Growth Factor Receptor-4 and ErbB2 in Regulation of Cyclin D1 Translation

Cited by 61 publications

References 49 publications

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

Fibroblast Growth Factor Receptor Inhibitors as a Cancer Treatment: From a Biologic Rationale to Medical Perspectives

Combination of the FGFR4 inhibitor PD173074 and 5-fluorouracil reduces proliferation and promotes apoptosis in gastric cancer

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