Overexpression of Human HMW FGF-2 but Not LMW FGF-2 Reduces the Cytotoxic Effect of Lentiviral Gene Transfer in Human Corneal Endothelial Cells

Valtink, Monika; Knels, Lilla; Stanke, Nicole; Engelmann, Katrin; Funk, Richard; Lindemann, Dirk

doi:10.1167/iovs.12-9423

Cited by 8 publications

(5 citation statements)

References 41 publications

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“…For example, FGF-2 overexpression in transgenic mice causes dysmorphic skeletal syndromes associated with high rates of osteoblast proliferation, suggesting that the membrane FGFR pathway may have greater importance in regulating FGF-23 expression in high bone turnover states (26). On the other hand, HMW-FGF-2 may have a growth arrest-inducing role (60), consistent with the possibility that INFS signaling may play an important role in non-replicating osteocytes.…”

Section: Discussionmentioning

confidence: 78%

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

Han

Xiao

Quarles

2015

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 78%

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

Han

Xiao

Quarles

2015

Journal of Biological Chemistry

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“…The sizes of immunoreactive bands were identical to those described in the literature[35], [44]. All patient tissue extracts examined (n = 60) contained both Hi- and Lo-FGF-2 isoforms, although the relative contribution, as well as absolute amount, of each type of isoform varied considerably between individuals.…”

Section: Discussionsupporting

confidence: 70%

“…All human Hi-FGF-2 isoforms, namely the 22, 22.5, 24 and 34 kDa proteins were produced by hMFs. The 34 kDa FGF-2 is a uniquely human isoform, which has not been detected previously in primary, non-transformed cells [35], [44]. It is possible that expression of 34 kDa FGF-2 occurs preferentially in human myofibroblasts, as it was not detected in primary human endothelial cells.…”

Section: Discussionmentioning

confidence: 75%

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High Molecular Weight Fibroblast Growth Factor-2 in the Human Heart Is a Potential Target for Prevention of Cardiac Remodeling

et al. 2014

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Fibroblast growth factor 2 (FGF-2) is a multifunctional protein synthesized as high (Hi-) and low (Lo-) molecular weight isoforms. Studies using rodent models showed that Hi- and Lo-FGF-2 exert distinct biological activities: after myocardial infarction, rat Lo-FGF-2, but not Hi-FGF-2, promoted sustained cardioprotection and angiogenesis, while Hi-FGF-2, but not Lo-FGF-2, promoted myocardial hypertrophy and reduced contractile function. Because there is no information regarding Hi-FGF-2 in human myocardium, we undertook to investigate expression, regulation, secretion and potential tissue remodeling-associated activities of human cardiac (atrial) Hi-FGF-2. Human patient-derived atrial tissue extracts, as well as pericardial fluid, contained Hi-FGF-2 isoforms, comprising, respectively, 53%(±20 SD) and 68% (±25 SD) of total FGF-2, assessed by western blotting. Human atrial tissue-derived primary myofibroblasts (hMFs) expressed and secreted predominantly Hi-FGF-2, at about 80% of total. Angiotensin II (Ang II) up-regulated Hi-FGF-2 in hMFs, via activation of both type 1 and type 2 Ang II receptors; the ERK pathway; and matrix metalloprotease-2. Treatment of hMFs with neutralizing antibodies selective for human Hi-FGF-2 (neu-AbHi-FGF-2) reduced accumulation of proteins associated with fibroblast-to-myofibroblast conversion and fibrosis, including α-smooth muscle actin, extra-domain A fibronectin, and procollagen. Stimulation of hMFs with recombinant human Hi-FGF-2 was significantly more potent than Lo-FGF-2 in upregulating inflammation-associated proteins such as pro-interleukin-1β and plasminogen-activator-inhibitor-1. Culture media conditioned by hMFs promoted cardiomyocyte hypertrophy, an effect that was prevented by neu-AbHi-FGF-2 in vitro. In conclusion, we have documented that Hi-FGF-2 represents a substantial fraction of FGF-2 in human cardiac (atrial) tissue and in pericardial fluid, and have shown that human Hi-FGF-2, unlike Lo-FGF-2, promotes deleterious (pro-fibrotic, pro-inflammatory, and pro-hypertrophic) responses in vitro. Selective targeting of Hi-FGF-2 production may, therefore, reduce pathological remodelling in the human heart.

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“…For infection, exponentially growing T47D-YA cells were mixed for 48 h with lentiviral particles previously diluted 1:2 with fresh medium in the presence of 0.8 μg/mL polybrene (Sigma-Aldrich) in a six-well plate. T47D-YA were stably infected with p6NST50 (empty vector), FGF2-18 kDa, or FGF2-22.5 kDa plasmids [18], monitored for GFP expression and selected with zeocin (Invivogen; 300 μg/mL).…”

Section: Preparation Of Lentiviral Particles and Stable T47d-ya Infec...mentioning

confidence: 99%

Increased High Molecular Weight FGF2 in Endocrine-Resistant Breast Cancer

et al. 2018

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Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.

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Overexpression of Human HMW FGF-2 but Not LMW FGF-2 Reduces the Cytotoxic Effect of Lentiviral Gene Transfer in Human Corneal Endothelial Cells

Cited by 8 publications

References 41 publications

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

Membrane and Integrative Nuclear Fibroblastic Growth Factor Receptor (FGFR) Regulation of FGF-23

High Molecular Weight Fibroblast Growth Factor-2 in the Human Heart Is a Potential Target for Prevention of Cardiac Remodeling

Increased High Molecular Weight FGF2 in Endocrine-Resistant Breast Cancer

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