Inhibition of Cell Migration by 24-kDa Fibroblast Growth Factor-2 Is Dependent upon the Estrogen Receptor

Piotrowicz, Randolph S.; Ding, Lan; Maher, Pamela; Levin, Eugene G.

doi:10.1074/jbc.m004868200

Cited by 17 publications

(18 citation statements)

References 47 publications

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“…However, our data (Fig. 5) indicate that ATEϩ31 has no effect on the constitutive levels of ERK phosphorylation and that 24kD FGF-2 stimulates ERK phosphorylation in the same manner as 18kD FGF-2 (16).…”

Section: Figmentioning

confidence: 43%

“…5). In both MCF-7 cells and endothelial cells 24kD FGF-2, at a concentration of 4 ϫ 10 Ϫ11 M, stimulated the phosphorylation of ERK1/2, a response that also occurs in 3T3 cells (16). However, at the same molar concentration MCF-7 and endothelial cells were treated with 1 ng/ml 24kD FGF-2 or 0.37 ng/ml ATEϩ31 for 10 min, the cells were extracted, and the protein lysates were immunoblotted with antibodies to either phospho-ERK (phospho) or total ERK.…”

Section: Figmentioning

confidence: 99%

“…In previous studies, it was shown that the FGF receptor to which 24kD FGF-2 binds in endothelial, MCF-7, and 3T3 cells is FGFR1 (16). To determine whether ATEϩ31 contains a major binding domain for interaction with FGFR1, competition binding experiments were performed with iodinated 24kD FGF-2 versus unlabeled 24kD FGF-2, 18kD FGF-2, or ATEϩ31 (Fig.…”

Section: Figmentioning

confidence: 99%

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Inhibition of Cell Migration and Angiogenesis by the Amino-terminal Fragment of 24kD Basic Fibroblast Growth Factor

Ding

Doñate

Parry

et al. 2002

Journal of Biological Chemistry

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The 24-kDa form of basic fibroblast growth factor inhibits the migration of endothelial cells and mammary carcinoma cells while continuing to promote cell proliferation. This molecule consists of the 18-kDa fibroblast growth factor sequence plus an additional 55 amino acids at the amino-terminal end. Antibody neutralization studies suggested that the inhibition of migration is associated with these 55 amino acids, whereas the promotion of proliferation localizes to the 18-kDa domain. To determine whether 24kD basic fibroblast growth factor could be modified to eliminate its effect on cell proliferation but retain its inhibition of migration, portions of the carboxyl-terminal end of 24kD fibroblast growth factor were deleted, and the products were tested on MCF-7 and endothelial cells. A protein consisting of the 55 amino acids of the amino-terminal end and the first 31 amino acids of 18kD basic fibroblast growth factor (ATE؉31) inhibited migration by 80% but did not promote cell growth. Arginine to alanine substitutions within the first 21 amino acids of the carboxyl-terminal end substantially reduced the efficacy of ATE؉31, whereas substitutions in the remaining part of the molecule had no effect. Competition binding experiments showed that ATE؉31 does not compete with 24kD basic fibroblast growth factor for binding to fibroblast growth factor receptor 1. In an in vivo matrigel plug assay, 150 nM ATE؉31 peptide reduced angiogenesis by 80%. These studies demonstrate that the amino-terminal end of 24kD basic fibroblast growth factor is responsible for an activity that inhibits the migration rates of cultured cells as well as the angiogenic response in vivo. Basic fibroblast growth factor (FGF-2)1 is a mitogen produced and secreted by endothelial cells, which promotes cell proliferation, chemotaxis, protease production, and integrin expression (1-4). As a consequence, it is an integral component of the angiogenic process. FGF-2 is mitogenic for a number of cells of different types including endothelial cells, fibroblasts (3T3 cells), and mammary carcinoma cells (MCF-7) (5, 6). It has been implicated in cell proliferation and migration during development, wound healing, and tumor growth, and it inhibits apoptosis of endothelial cells (1,(7)(8)(9)(10)(11)(12). A single copy gene for FGF-2 encodes for multiple forms of the protein of 24, 22.5, 22, and 18 kDa with the three higher molecular weight isoforms produced by initiation of translation at three CUG codons located upstream from the classical AUG initiation site (13, 14). 24kD FGF-2 consists of the 18-kDa isoform plus an additional 55 amino acids at the amino-terminal end (ATE).In a recent publication, we demonstrated that endothelial cells could be stimulated to secrete the high molecular weight FGF-2 forms in a regulated manner and to levels capable of affecting cell behavior (5). The effects were 2-fold; these were stimulation of cell proliferation and inhibition of migration. The increase in proliferation was comparable with that promoted by 18kD FGF-2, indi...

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Section: Figmentioning

confidence: 43%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

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Inhibition of Cell Migration and Angiogenesis by the Amino-terminal Fragment of 24kD Basic Fibroblast Growth Factor

Ding

Doñate

Parry

et al. 2002

Journal of Biological Chemistry

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“…4B (top) showed that wild-type ER is mostly nuclear, whereas its mutant seems to be more abundant in the cytoplasmic fractions, generally consistent with the immunostaining results. Endogenous ER protein was also previously found to be both cytosolic and nuclear in ER + MCF-7 cells by cell fractionation experiments (52). Of great interest, nuclear p38g protein is decreased upon ER induction, whereas its levels in cytoplasm remain constant.…”

Section: ) In Ermentioning

confidence: 95%

p38γ Mitogen-Activated Protein Kinase Integrates Signaling Crosstalk between Ras and Estrogen Receptor to Increase Breast Cancer Invasion

Tang

Loesch

et al. 2006

Cancer Research

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Ras is believed to stimulate invasion and growth by different effector pathways, and yet, the existence of such effectors under physiologic conditions has not been shown. Estrogen receptor (ER), on the other hand, is both anti-invasive and proliferative in human breast cancer, with mechanisms for these paradoxical actions remaining largely unknown. Our previous work showed an essential role of p38; mitogenactivated protein kinase in Ras transformation in rat intestinal epithelial cells, and here, we show that p38; integrates invasive antagonism between Ras and ER to increase human breast cancer invasion without affecting their proliferative activity. Ras positively regulates p38; expression, and p38; in turn mediates Ras nonmitogenic signaling to increase invasion. Expression of the Ras/p38; axis, however, is trans-suppressed by ER that inhibits invasion and stimulates growth also by distinct mechanisms. Analysis of ER and its cytoplasmic localized mutant reveals that ER additionally binds to p38; protein, leading to its specific down-regulation in the nuclear compartment. A p38;-antagonistic activity of ER was further shown in a panel of breast cancer cell lines and was shown independent of estrogens by both ER depletion and ER expression. These results revealed that both Ras and ER use distinct pathways to regulate breast cancer growth and invasion, and that p38; specifically integrates their antagonistic activity to stimulate cell invasion. Selective targeting of p38;-dependent invasion pathways may be a novel strategy to control breast cancer progression. (Cancer Res 2006; 66(15): 7540-7)

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“…20 Using specific antibodies, they localized the inhibition of migration to the amino-terminal end and stimulation of growth to the 18-kDa domain of 24-kDa FGF2. They concluded that 24-kDa FGF2 affects cell behavior differently than 18-kDa FGF2.…”

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confidence: 99%

Role of Fibroblast Growth Factor-2 Isoforms in the Effect of Estradiol on Endothelial Cell Migration and Proliferation

Garmy‐Susini

Delmas

Gourdy

et al. 2004

Circulation Research

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Abstract-Both 17␤-estradiol (E 2 ) and fibroblast growth factor-2 (FGF2) stimulate angiogenesis and endothelial cell migration and proliferation. The first goal of this study was to explore the potential link between this hormone and this growth factor. E 2 -stimulated angiogenesis in SC Matrigel plugs in Fgf2 ϩ/ϩ mice, but not in Fgf2 Ϫ/Ϫ mice. Cell cultures from subcutaneous Matrigel plugs demonstrated that E 2 increased both migration and proliferation in endothelial cells from Fgf2 ϩ/ϩ mice, but not from in Fgf2 Ϫ/Ϫ mice. Several isoforms of fibroblast growth factor-2 (FGF2) are expressed: the low molecular weight 18-kDa protein (FGF2 lmw ) is secreted and activates tyrosine kinase receptors (FGFRs), whereas the high molecular weight (21 and 22 kDa) isoforms (FGF2 hmw ) remains intranuclear, but their role is mainly unknown. The second goal of this study was to explore the respective roles of FGF2 isoforms in the effects of E 2 . We thus generated mice deficient only in the FGF2 lmw (Fgf2 lmwϪ/Ϫ ). E 2 stimulated in vivo angiogenesis and in vitro migration in endothelial cells from Fgf2 lmwϪ/Ϫ as it did in Fgf2 ϩ/ϩ mice. E 2 increased FGF2 hmw protein abundance in endothelial cell cultures from Fgf2 ϩ/ϩ and Fgf2 lmwϪ/Ϫ mice. As shown using siRNA transfection, these effects were FGFR independent but involved FGF2-Interacting Factor, an intracellular FGF2 hmw partner. This is the first report for a physiological role for the intracellular FGF2 hmw found to mediate the effect of E 2 on endothelial cell migration via an intracrine action. Key Words: mouse Ⅲ estradiol Ⅲ growth factor Ⅲ endothelium Ⅲ migration E ndothelium, being uniquely positioned at the interface between the blood and the vessel wall, plays a crucial role in the physiology of circulation by performing multiple functions. 1,2 It is involved in the regulation of coagulation, leukocyte adhesion in inflammation, transvascular flux of cells, liquids, and solutes, vessel tone, and vascular smooth muscle growth. Endothelium also constitutes a target for the sex hormone, 17␤-estradiol (E 2 ). Using a series of experimental models, E 2 has been reported to promote angiogenic activity and endothelial cell migration and proliferation. 3 The angiogenic effect is mediated through the estrogen receptor ␣ (ER␣). 4 However, the mechanisms involved downstream of ER␣ remain unclear. 5 Fibroblast growth factor-2 (FGF2) is an important mitogenic and angiogenic factor that stimulates endothelial cell growth and migration. Therefore, FGF2 could be a good candidate to be a partner of E 2 . However, FGF2 expression is complex because at least four (18, 22, 22.5, and 24 kDa) in human and three (18, 21, and 22 kDa) FGF2 isoforms in mouse are synthesized through the alternative use of translation initiation codons. 6 -9 These isoforms differ only in their NH 2 extremities, which confer a nuclear localization to the high molecular weight CUG-initiated (22, 22.5, 24 or 21, and 22 kDa) isoforms (FGF2 hmw ), whose function is mainly unknown. In contrast, the smaller 18-kDa A...

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Inhibition of Cell Migration by 24-kDa Fibroblast Growth Factor-2 Is Dependent upon the Estrogen Receptor

Cited by 17 publications

References 47 publications

Inhibition of Cell Migration and Angiogenesis by the Amino-terminal Fragment of 24kD Basic Fibroblast Growth Factor

Inhibition of Cell Migration and Angiogenesis by the Amino-terminal Fragment of 24kD Basic Fibroblast Growth Factor

p38γ Mitogen-Activated Protein Kinase Integrates Signaling Crosstalk between Ras and Estrogen Receptor to Increase Breast Cancer Invasion

Role of Fibroblast Growth Factor-2 Isoforms in the Effect of Estradiol on Endothelial Cell Migration and Proliferation

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