Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression.
TL;DR: It is shown that increased receptor stability and sustained FGFR-4 signaling occur in most human prostate cancers due to either the presence of a common genetic polymorphism or the expression of a protein that stabilizes FG FR-4.
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About: This article is published in Neoplasia. The article was published on 01 Aug 2008. and is currently open access. The article focuses on the topics: Fibroblast growth factor receptor 4 & Prostate cancer.
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Figures
Figure 5. Stabilization of FGFR-4 Gly388 by HIP1. 293T cells were transfected with V5-tagged FGFR-4 Arg388 or Gly388 with or without HIP1, and cell surface receptors were labeled with biotin. Cells were then stimulated with FGF2 and lysed at the indicated time. Labeled receptors were then immunoprecipitated with streptavidin– agarose, and FGFR-4 was detected by Western blot of the immunoprecipitates with anti-V5 antibody. 
Figure 6. Direct interaction of FGFR-4 and HIP1. (A) 293T cells were transfected with Flag-tagged HIP1 or N-terminally truncated HIP1 (−183) with or without either FGFR-4 Arg388 or Gly388 (both V5-tagged). Vector control (Tag2B) is also shown. Cell lysates were then analyzed by Western blot using anti-V5 or anti-Flag antibody or were used for reciprocal immunoprecipitation and Western blot analysis with the two antibodies. (B) Map of HIP1 showing major domains and deletion fragments used to prepare bacterial fusion proteins. (C) Purified HIP1 and HIP1 deletion bacterial fusion proteins on Coomassie blue–stained polyacrylamide gel after electrophoreisis. (D) 293T cells were transfected with V5-tagged FGFR-4 and lysates prepared and incubated with purified HIP1 and HIP1 deletion constructs. Complexes were then immunoprecipitated with streptavidin beads, and Western blot was performed with anti-V5 antibody. Control is streptavidin beads but no purified protein. 
Figure 7. Biologic affects of HIP1 in prostate and prostate cancer cell lines. (A) Prostate (PNT1A) or prostate cancer (DU145) cell lines expressing full-length HIP1, an amino terminal–truncated HIP1 (NT) or vector only were plated, and growth was determined in a defined medium containing FGF2 and insulin as the only growth factors. Cell number was determined at 2-day intervals. Mean ± SD of triplicates is shown. (B) PNT1A cells overexpressing HIP1 were infected with lentivirus expressing ShRNA targeting HIP1 or FGFR-4, and stable expressors were selected and pooled. Quantitative RT-PCR showed 70% and 60% knockdown of HIP1 and FGFR-4 mRNA, respectively (data not shown). Cells were then plated, and grown was determined in defined medium with FGF2 and insulin as the only growth factors or serum-containing medium. Cell number was determined at 2-day intervals by cell counting. Mean ± SD of triplicates is shown. (C) PNT1A cells as described in (B) were plated in soft agar. Colony formation was evaluated by counting. Mean ± SD of triplicates is shown. 
Figure 1. Increased stability of the FGFR-4 Arg388 variant after ligand stimulation. 293T cells were transfected with V5-tagged FGFR-4 Arg388 or Gly388 and cell surface receptors labeled with biotin. Cells were then stimulated with FGF2 and lysed at the indicated time. Labeled receptors were then immunoprecipitated with streptavidin–agarose and FGFR-4 detected by Western blot of the immunoprecipitates with anti-V5 antibody. Western blot of an aliquot of the lysate used for immunoprecipitation with anti–βactin antibody is shown. 
Figure 2. Sustained phosphorylation of the FGFR-4 Arg388 variant after ligand stimulation. (A) PNT1A cells expressing V5-tagged FGFR-4 Arg388 or Gly388 were seeded at 2.5 × 106 in 60-mm diameter culture dishes in complete medium. Cells were gently scraped with a plastic tip. Themediumwas removed, and cellswerewashed twice with PBS. Complete medium was added, and cells were allowed to scatter/migrate into the area of clearing for a total of 40 hours, and photomicrographs were taken at 0-, 24-, and 40-hour time points. Scratch assays were performed four times, and representative results are shown. (B) PNT1A cells expressing either V5-tagged FGFR-4Arg388 (AA) or Gly388 (GG)were plated. After overnight incubation in medium with insulin as the only growth factor, cells were stimulated with FGF2 and lysates were prepared at the indicated times. Tagged FGFR-4 was immunoprecipitated with an anti-V5 antibody, and the phosphorylated receptor was detected by Western blot of immunoprecipitates with anti–phospho-FGF-R antibody (Tyr641/642). Western blot with anti-V5 antibody is shown to confirm equivalent immunoprecipitation. 
Figure 4. Stabilization of FGFR-4 by HIP1 in prostate epithelial and prostate cancer cells. Immortalized normal prostate epithelial cells (PNT1A) or prostate cancer cells (LNCaP) were transfected with HIP1 in the TOPO-V5 expression vector and stable cells lines selected. (A) Expression of HIP1 and FGFR-4 protein was evaluated by Western blot with β-actin as a loading control. (B) Expression of FGFR-4 mRNA was determined by quantitative RT-PCR with normalization to β-actin transcript levels.
Citations
Identification of a novel oncogenic mutation of FGFR4 in gastric cancer
Takashi Futami,Tatsuya Kawase,Kenichi Mori,Makoto Asaumi,Rumi Kihara,Nobuaki Shindoh,Sadao Kuromitsu +6 more
TL;DR: The identification of an oncogenic mutation in FGFR4 in a human gastric tumour that leads to constitutive activation of its product,FGFR4 is reported, and results demonstrate that mutationally activated FGFR 4 acts as an oncoprotein.
Type 2 Diabetes, Obesity, and Cancer Share Some Common and Critical Pathways.
TL;DR: This review article has presented the recent and most updated evidence from the studies where the origin, biological background, and correlation between type 2 diabetes and cancer have been presented or proved, and summarized the methodological challenges and tasks that are frequently encountered.
The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling
TL;DR: These results identify a compelling link betweenFGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect onNFκB signaling including an inhibitory effect on proapoptotic signaling.
FGFR4 transmembrane domain polymorphism and cancer risk: A meta-analysis including 8555 subjects
TL;DR: The meta-analysis suggests that the FGFR4 Gly388Arg polymorphism most likely contributes to susceptibility to cancer, especially in Asians and the Arg(388) allele might be associated with increased risks of breast and prostate cancer.
Role of fibroblast growth factor receptor 4 in cancer
TL;DR: In this review, the recent findings in FGFR4 structure, signaling transduction, physiological function, aberrant regulations, and effects in cancers as well as its potential applications as an anticancer therapeutic target are summarized.
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Expression of Variant TMPRSS2/ERG Fusion Messenger RNAs Is Associated with Aggressive Prostate Cancer
TL;DR: Both the isoforms of TMPRSS2/ERG fusions expressed and expression level may affect prostate cancer progression, and in this group, higher expression levels of fusion mRNA were present in cancers with early prostate-specific antigen recurrence.
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