Phosphorylation of Insulin-Like Growth Factor Binding Protein-3 by Deoxyribonucleic Acid-Dependent Protein Kinase Reduces Ligand Binding and Enhances Nuclear Accumulation

Schedlich, Lynette J.; Nilsen, Trine; John, Anna; Jans, David A.; Baxter, Robert C.

doi:10.1210/en.2002-220798

Cited by 49 publications

(53 citation statements)

References 40 publications

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“…The mechanism involves interaction with Importin Beta (Schedlich et al, 2003), a gene not previously recognised to be regulated by hypoxia, which was induced by hypoxia in our study (4.1-fold) in vitro. Thus, induction of IGFBP3 may have a more complex role then previously reported.…”

Section: Discussionsupporting

confidence: 47%

“…In contrast to its extracellular IGF-binding role, an intracellular role of IGFBP-3 has been described (Schedlich et al, 2003), with phosphorylation increasing nuclear import of IGFBP-3, with release of IGF. The mechanism involves interaction with Importin Beta (Schedlich et al, 2003), a gene not previously recognised to be regulated by hypoxia, which was induced by hypoxia in our study (4.1-fold) in vitro.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer

et al. 2005

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Hypoxia-inducible genes have been linked to the aggressive phenotype of cancer. However, nearly all work on hypoxia-regulated genes has been conducted in vitro on cell lines. We investigated the hypoxia transcriptome in primary human bladder cancer using cDNA microarrays to compare genes induced by hypoxia in vitro in bladder cancer cell line EJ28 with genes upregulated in 39 bladder tumour specimens (27 superficial and 12 invasive). We correlated array mRNA fold changes with carbonic anhydrase 9 (CA IX) staining of tumours as a surrogate marker of hypoxia. Of 6000 genes, 32 were hypoxia inducible in vitro more than two-fold, five of which were novel, including lactate transporter SLC16A3 and RNAse 4. Eight of 32 hypoxia-inducible genes in vitro were also upregulated on the vivo array. Vascular endothelial growth factor mRNA was upregulated two-fold by hypoxia and 2 -18-fold in 31 out of 39 tumours. Glucose transporter 1 was also upregulated on both arrays mRNA, and fold changes on the in vivo array significantly correlated with CA IX staining of tumours (P ¼ 0.008). However, insulin-like growth factor binding protein 3 mRNA was the most strongly differentially expressed gene in both arrays and this confirmed its upregulation in urine of bladder cancer patients (n ¼ 157, Po0.01). This study defines genes suitable for an in vivo hypoxia 'profile', shows the heterogeneity of the hypoxia response and describes new hypoxia-regulated genes.

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Section: Discussionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer

et al. 2005

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“…IGFBP-5 nuclear localization has been reported in human breast carcinoma cell lines, 27 Chinese hamster ovary cells, 33 and porcine vascular smooth muscle cells. 34 We previously reported nuclear localization of IGFBP-5 in primary fibroblasts from fibrotic lung tissues, but not those from normal tissues. 17 We now show that IGFBP-5 translocates to the nucleus of IGFBP-5-expressing cells in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 90%

The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Yasuoka

Hsu

Ruiz

et al. 2009

The American Journal of Pathology

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We have previously shown that insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) is overexpressed in lung fibrosis and induces the production of extracellular matrix components, such as collagen and fibronectin, both in vitro and in vivo. The exact mechanism by which IGFBP-5 exerts these novel fibrotic effects is unknown. We thus examined the signaling cascades that mediate IGFBP-5-induced fibrosis. We demonstrate for the first time that

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“…It has been reported that human vitamin D receptor is phosphorylated at Ser 182 leading to an attenuation of its transactivation activity (43). Phosphorylation of IGFBP-3 has been shown to be involved in its nuclear translocation as well (44). By searching for the potential phosphorylation sites using the NetPhos 2.0 server (www.cbs.…”

Section: Discussionmentioning

confidence: 99%

Several Acidic Amino Acids in the N-domain of Insulin-like Growth Factor-binding Protein-5 Are Important for Its Transactivation Activity

Zhao

Yin

Bach

et al. 2006

Journal of Biological Chemistry

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Insulin-like growth factor-binding protein (IGFBP)-5 is a secreted protein that binds to IGFs and modulates IGF actions. IGFBP-5 is also found in the nuclei of cultured cells and has transactivation activity.Here we report the nuclear localization of endogenous IGFBP-5 in mouse embryonic skeletal cells. Chromatin immunoprecipitation experiments indicated that IGFBP-5 interacts with the nuclear histone-DNA complex. Using a series of deletion mutants, the transactivation domain of IGFBP-5 was mapped to its N-terminal region. Intriguingly, the transactivation activity of IGFBP-5 is masked by negative regulatory elements located in the L-and C-domains. Among the other IGFBPs, the N-domains of IGFBP-2 and -3 also had strong transactivation activity, whereas those of IGFBP-1 and -6 had no activity. The IGFBP-4 N-domain had modest activity. Sequence analysis revealed several amino acids in the IGFBP-5 N-domain that are not present in IGFBP-1. The activities of mutants in which these residues were changed to the corresponding IGFBP-1 sequence were determined. Mutations that changed acidic residues to neutral residues (e.g. E8A, D11S, E12A, E30S/P31A, E43L, and E52A) or a polar to a basic residue (e.g. Q56R) significantly reduced transactivation activity. The E8A/D11S/E12A triple mutant and E52A/Q56R double mutants showed further reduced activity. The combinatory mutants had essentially no transactivation activity. Taken together, our results indicate that there are several conserved residues in the IGFBP-5 N-terminal region that are critical for transactivation and that IGFBP-2 and -3 also have strong transactivation activity in their N-domains.The insulin-like growth factor (IGF) 2 system, consisting of two ligands (IGF-I and -II), two receptors (the IGF-I receptor and IGF-II receptor), and six high affinity IGF-binding proteins (IGFBPs), converges on a conserved signaling pathway that plays fundamental roles in vertebrate development and physiology and is implicated in several human diseases (1). The bioavailability and bioactivity of IGFs are regulated by their interactions with various members of the IGFBP family. IGFBPs all have a highly cysteine-rich N-terminal (N)-domain, a cysteine-rich C-terminal (C)-domain, and a middle linker (L)-domain with no cysteine residues except in IGFBP-4. The N-and C-domains are highly conserved within the IGFBP family, whereas the L-domain varies both within the family and across species.Besides binding to IGF and modulating its actions, IGFBP-5 has been reported to regulate cell proliferation (2, 3), migration (4 -6), and apoptosis/survival (7-11) independent of IGF. Although the ligand-dependent actions of IGFBP-5 are attributed to its interactions with the IGF ligand and other proteins (1), the mechanistic basis of the ligand-independent actions of IGFBP-5 is not yet understood.Andress et al. (12) used IGFBP-5 affinity chromatography to purify a 420-kDa membrane protein from human osteoblast cells and proposed that it was an IGFBP-5 receptor. The same study reported that IGFBP-5 ...

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Phosphorylation of Insulin-Like Growth Factor Binding Protein-3 by Deoxyribonucleic Acid-Dependent Protein Kinase Reduces Ligand Binding and Enhances Nuclear Accumulation

Cited by 49 publications

References 40 publications

Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer

Comparison of hypoxia transcriptome in vitro with in vivo gene expression in human bladder cancer

The Fibrotic Phenotype Induced by IGFBP-5 Is Regulated by MAPK Activation and Egr-1-Dependent and -Independent Mechanisms

Several Acidic Amino Acids in the N-domain of Insulin-like Growth Factor-binding Protein-5 Are Important for Its Transactivation Activity

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