PAPA-1 Is a Nuclear Binding Partner of IGFBP-2 and Modulates Its Growth-Promoting Actions

Miyako, Kenichi; Cobb, Laura J.; Francis, Malik Joseph; Huang, Alden; Peng, Bonnie; Pintar, John E.; Ariga, Hiroyoshi; Cohen, Pinchas

doi:10.1210/me.2008-0168

Cited by 29 publications

(19 citation statements)

References 30 publications

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“…17,20 IGFBP-2 was also reported to transmit signals independently of IGF-I/II by affecting cell adhesion via integrin binding, [21][22][23] and even to act in the cell nucleus. 24 In addition, increased levels of IGFBP-2 in the serum of cancer patients was shown in a variety of human cancers to be an indication of poor prognosis, [25][26][27][28][29] including CRC patients. [30][31][32][33] A recent study identified IGFBP-2 signaling as an important factor in the recruitment of endothelial cells in metastatic breast cancer by a miR-126-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression

et al. 2012

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1L1, a neuronal cell adhesion receptor of the immunoglobulin-like protein family is expressed in invading colorectal cancer (CRC) cells as a target gene of Wnt/b-catenin signaling. Overexpression of L1 in CRC cells enhances cell motility and proliferation, and confers liver metastasis. We recently identified ezrin and the IkB-NF-kB pathway as essential for the biological properties conferred by L1 in CRC cells. Here, we studied the underlying molecular mechanisms and found that L1 enhances ezrin phosphorylation, via Rho-associated protein kinase (ROCK), and is required for L1-ezrin co-localization at the juxtamembrane domain and for enhancing cell motility. Global transcriptomes from L1-expressing CRC cells were compared with transcriptomes from the same cells expressing small hairpin RNA (shRNA) to ezrin. Among the genes whose expression was elevated by L1 and ezrin we identified insulin-like growth factor-binding protein 2 (IGFBP-2) and showed that its increased expression is mediated by an NF-kB-mediated transactivation of the IGFBP-2 gene promoter. Expression of a constitutively activated mutant ezrin (Ezrin567D) could also increase IGFBP-2 levels in CRC cells. Overexpression of IGFBP-2 in CRC cells lacking L1-enhanced cell proliferation (in the absence of serum), cell motility, tumorigenesis and induced liver metastasis, similar to L1 overexpression. Suppression of endogenous IGFBP-2 in L1-transfected cells inhibited these properties conferred by L1. We detected IGFBP-2 in a unique organization at the bottom of human colonic crypts in normal mucosa and at increased levels throughout human CRC tissue samples co-localizing with the phosphorylated p65 subunit of NF-kB. Finally, we found that IGFBP-2 and L1 can form a molecular complex suggesting that L1-mediated signaling by the L1-ezrin-NF-kB pathway, that induces IGFBP-2 expression, has an important role in CRC progression.Oncogene ( In recent studies, we identified members of the immunoglobulin-like cell adhesion receptors (Nr-CAM and L1), mostly known for their function in nerve cells, 3,4 but also in many cancer cell types, 5 as target genes of b-catenin-TCF signaling in CRC cells. 6,7 We detected L1 in a subpopulation of cells at the invasive front of CRC tissue displaying nuclear b-catenin localization. 7 We further found that the expression of L1 in human CRC cells, lacking endogenous L1, confers enhanced motility and metastasis to the liver in a mouse metastasis model.

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Section: Discussionmentioning

confidence: 99%

Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression

et al. 2012

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“…It has been used as a prognostic marker in prostate cancer, which suggests a link between this group of proteins and prostate carcinogenesis. INO80B induces growth arrest by halting the cell cycle at the G1phase (Miyako et al, 2009; Kuroda et al, 2004). The effect of the POP chemical HCB was studied in detail in NIH 3T3 (mouse) and WS1 (human) embryonic cells.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the toxicogenomic effects of exposure to persistent organic pollutants (POPs) in Slovakian girls: Correlations between gene expression and disease risk

Mitra

Ghosh

Zang

et al. 2012

Environment International

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The chemical composition of Persistent Organic Pollutants (POPs) in the environment is not uniform throughout the world, and these contaminants contain many structurally different lipophilic compounds. In a well-defined study cohort in the Slovak Republic, the POP chemicals present in the peripheral blood of exposed children were chemically analyzed. The chemical analysis data revealed that the relative concentration and profile of structurally different organic pollutants, including polychlorinated biphenyls (PCBs), 2,2’-bis(4-chlorophenyl)-1,1- dichloroethylene (p,p’-DDE), 2,2’-bis(4-chlorophenyl)-1,1,1-trichloro-ethane (p,p’-DDT), hexachlorobenzene (HCB) and β-hexachlorocyclohexane (β-HCH), may vary from individual to individual, even within the same exposure area. These chemicals can be broadly classified into two groups. The first group, the PCB congeners, primarily originated from industrial compounds and their byproducts. The second group of compounds originated from or was commonly used in the agricultural sector (e.g., DDT, HCB). The objective of this study was to examine the effects of the two POP exposure profiles on gene expression. For the study population, we selected prepubertal girls (mean age of 46.2 ± 1.4 months) with high POP concentrations in their blood (> 75% tile of total POP) and classified them in the high ‘PCB’ group when the total PCB concentration was significantly higher than the total concentration of other POP components and in the ‘Other Than PCB’ (OTP) group, when the total PCB concentration was significantly lower than the concentration of the other major POP constituents. A matched control group of girls (< 25% tile of total POP) was selected for comparison purpose (n = 5 per group). Our aims were to determine whether there were any common effects of high POP exposure at a toxicogenomic level and to investigate how exposure may affect physiological functions of the children in two different exposure scenarios. Global gene expression analysis using a microarray (Affymetrix Gene Chip Human genome U133 Plus 2.0 Array) platform was conducted on the total RNA of peripheral blood mononuclear cells from the girls. The results were analyzed by Partek GS, Louis, MI, which identified twelve genes (ATAD2B, BIVM, CD96, CXorf39, CYTH1 ETNK1, FAM13A, HIRA, INO80B, ODG1, RAD23B, and TSGA14) and two unidentified probe sets, as regulated differentially in both the PCB and OTP groups against the control group. The qRT-PCR method was used to validate the microarray results. The Ingenuity Pathway Analysis (IPA) software package identified the possible molecular impairments and disease risks associated with each gene set. Connective tissue disorders, genetic disorders, skeletal muscular disorders and neurological diseases were associated with the 12 common genes. The data therefore identified the potential molecular effects of POP exposure on a genomic level. This report underscores the importance of further study to validate the results in a random population and to evaluate the use of the identif...

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“…In addition, IGFBP-2 has been reported to be localized on the cell surface, in the cytoplasm and on the nuclear membrane [14]. Several groups have now reported nuclear localisation of IGFBP-2 [15][16][17]. A functional nuclear localisation sequence in the central domain of IGFBP-2 has been reported that appears to interact with importin-α [18].…”

Section: Igfbp-2mentioning

confidence: 99%

IGFBP-2/PTEN: A critical interaction for tumours and for general physiology?

Zeng

Perks

Holly

2015

Growth Hormone & IGF Research

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PAPA-1 Is a Nuclear Binding Partner of IGFBP-2 and Modulates Its Growth-Promoting Actions

Cited by 29 publications

References 30 publications

Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression

Global analysis of L1-transcriptomes identified IGFBP-2 as a target of ezrin and NF-κB signaling that promotes colon cancer progression

Analysis of the toxicogenomic effects of exposure to persistent organic pollutants (POPs) in Slovakian girls: Correlations between gene expression and disease risk

IGFBP-2/PTEN: A critical interaction for tumours and for general physiology?

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