Insulin-Like Growth Factor Binding Protein-2: Contributions of the C-Terminal Domain to Insulin-Like Growth Factor-1 Binding

Kibbey, Megan M.; Jameson, Mark J.; Eaton, Erin M.; Rosenzweig, Steven A

doi:10.1124/mol.105.016998

Cited by 29 publications

(64 citation statements)

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“…Because the C-terminus of IGFBP2 is involved in both IGF binding 39 and IGF-independent signaling, 40 we sought to determine whether IGFBP2's effect on HSCs depended on IGF signaling. Here, we compared the repopulation of IGF-IR-null donor cells in WT and IGFBP2-null recipients.…”

Section: The C-terminus Of Igfbp2 Is Important For Supporting Hsc Actmentioning

confidence: 99%

IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells

Huynh

Zheng

Umikawa

et al. 2011

Blood

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The role of IGF binding protein 2 (IGFBP2) in cell growth is intriguing and largely undefined. Previously we identified IGFBP2 as an extrinsic factor that supports ex vivo expansion of hematopoietic stem cells (HSCs). Here we showed that IGFBP2-null mice have fewer HSCs than wild-type mice. While IGFBP2 has little cell-autonomous effect on HSC function, we found decreased in vivo repopulation of HSCs in primary and secondary transplanted IGFBP2-null recipients. Importantly, bone marrow stromal cells that are deficient for IGFBP2 have significantly decreased ability to support the expansion of repopulating HSCs. To investigate the mechanism by which IGFBP2 supports HSC activity, we demonstrated that HSCs in IGFBP2-null mice had decreased survival and cycling, down-regulated expression of antiapoptotic factor Bcl-2, and up-regulated expression of cell cycle inhibitors p21, p16, p19, p57, and PTEN. Moreover, we found that the C-terminus, IntroductionThe number of hematopoietic stem cells (HSCs) is determined by the balance among different cell fates-self-renewal, differentiation, apoptosis, and migration-which are regulated by the intrinsic factors and environmental cues in vivo or in vitro. 1,2 We have identified several growth factors and secreted proteins that support the repopulation of HSCs and have developed an efficient serumfree system to support ex vivo expansion of mouse and human HSCs. [3][4][5] Insulin-like growth factor binding protein 2 (IGFBP2) is one of these secreted proteins; we isolated IGFBP2 from a cancer line that supports ex vivo expansion of HSCs. 6,7 IGFBP2 is a member of the IGFBP family that is found in all vertebrates; it modulates the biologic effects of IGFs by controlling the distribution, function, and activity of IGF-1 and IGF-2. 8 IGFBP2 is expressed in the fetus and in several adult tissues and biologic fluids. It is also overexpressed in many tumors and in some cases its expression level correlates with grade of malignancy. [9][10][11] The level of IGFBP2 appears to be low in well-differentiated tumors but high in poorly differentiated tumors. 12 The known functions of IGFBP2 are very interesting. IGFBP2 displays IGF-dependent inhibitory effects on normal somatic cell growth. However, several studies demonstrated that IGFBP2 has intrinsic bioactivities that are independent of IGF-1 or IGF-2. IGFBP2 stimulates proliferation, survival, differentiation, and motility of various types of cells. 9,[13][14][15][16][17][18][19][20] Multiple mechanisms for these IGF-independent actions of IGFBP2 have been proposed. One line of studies supported the concept that intracellular IGFBP2 binds integrin and supports cell survival. 13 A second line of studies suggested that IGFBP2 acts as secreted proteins and binds to cell surface receptors. For example, when bound to the cell surface integrin, extrinsic IGFBP2 influences cell mobility and proliferation. [9][10][11]21 IGFBP2 also binds to Frizzled 8 and LDL receptorrelated protein 6 and is proposed to antagonize Wnt signaling in heart cells. 22...

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Section: The C-terminus Of Igfbp2 Is Important For Supporting Hsc Actmentioning

confidence: 99%

IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells

Huynh

Zheng

Umikawa

et al. 2011

Blood

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“…These studies show that in tumor cells leptin regulates the genes for other growth factors and receptors at the late time points evaluated. Leptin reduced the expression of TGFB1 and IGFBP2 genes, peptides known for their growth-inhibitory effects in mammary epithelial cells (Nam et al 1997, Kaaks 2001, Pereira et al 2004, Kibbey et al 2006, Buck & Knabbe 2006, Frommer et al 2006. Initial studies assigned dual and opposing roles for TGFB1 in tumor cells, both as a growth suppressor and as a component of the cell invasion signal cascade.…”

Section: Leptin Regulates Ecm and Cytoskeleton Genesmentioning

confidence: 99%

“…The ability of leptin to reduce IGFBP2 expression may contribute to breast tumorigenesis by two mechanisms. First, extracellular IGFBP2 competes with cell surface IGF receptors for binding to IGF1, a potent mitogen in tumor cells (Kaaks 2001, Kibbey et al 2006. Thus, lowered levels of antagonistic IGFBP2, which have been observed in obese subjects (Nam et al 1997), may lead to greater availability of IGF1 to its receptor resulting in tumor cell proliferation.…”

Section: Leptin Regulates Ecm and Cytoskeleton Genesmentioning

confidence: 99%

Leptin-regulated gene expression in MCF-7 breast cancer cells: mechanistic insights into leptin-regulated mammary tumor growth and progression

Perera¹,

Chin²,

Duru³

et al. 2008

Journal of Endocrinology

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Obesity is a recently established risk factor for breast cancer incidence and mortality. A characteristic of obesity is elevated circulating levels of adipocyte-derived hormone leptin. Evidence indicates that leptin plays an important role in mammary tumor formation; however, the mechanisms involved are poorly understood. Toward better defining the role of leptin in breast cancer, we describe the identification of leptin-regulated genes in hormone-responsive Michigan Cancer Foundation-7 (MCF-7) human breast cancer cells using a microarray system. More than 64 leptin-regulated genes were identified including those for growth factors, cell cycle regulators, extracellular matrix (ECM) proteins, and genes associated with metastasis. Cell cycle genes up-regulated by leptin include cyclins D and G, cyclin-dependent kinase 2, p21, p27, and p16. Leptin suppressed the expression of transforming growth factor-b , a cell cycle suppressor. Determining the significance of this effect, treatment of MCF-7 cells with TGFB1 abrogated leptin-stimulated proliferation. Leptin up-regulated the expression of connective tissue growth factor, villin 2, and basigin, factors that are associated with ECM and are known to impact tumor growth. Finally, leptin induced the expression of anti-apoptotic genes BCL2 and survivin, and reduced the expression of apoptotic genes. The effect of leptin on MCF-7 survival was evaluated via TUNEL assay and demonstrated a sixfold reduction in apoptosis in leptin-treated cells, compared with controls. These data suggest leptin promotes mammary tumor growth through multiple mechanisms, including regulating the cell cycle, apoptosis, and by modulating the extracellular environment. The identification of leptinregulated genes begins to provide mechanistic links into the relationship between obesity and breast cancer incidence and morbidity.

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“…IGFBP-2, the second most abundant IGFBP, exerts an inhibitory effect on cell growth and proliferation in the majority of normal tissues as a result of its ability to sequester IGFs (1,2). In contrast to its inhibitory effects in normal tissues, IGFBP-2 is associated with an increase in cell proliferation in cancer cell lines (3). Further, IGFBP-2 is expressed by many malignancies and often reflects an increasingly malignant tumor phenotype (3,4).…”

mentioning

confidence: 98%

“…In contrast to its inhibitory effects in normal tissues, IGFBP-2 is associated with an increase in cell proliferation in cancer cell lines (3). Further, IGFBP-2 is expressed by many malignancies and often reflects an increasingly malignant tumor phenotype (3,4). Increased serum IGFBP-2 concentrations have been reported in adult patients with liver (5), lung (6), colon (7), prostate (8), ovarian (9), adrenal (10), or non -islet cell pancreatic malignancies (11), and in children with central nervous system tumors (12) or acute lymphoblastic leukemia (12 -14).…”

mentioning

confidence: 99%

Evaluation of Plasma Insulin-like Growth Factor Binding Protein 2 and Her-2 Extracellular Domain as Biomarkers for 17-Allylamino-17-Demethoxygeldanamycin Treatment of Adult Patients with Advanced Solid Tumors

Eiseman

Guo

Ramanathan

et al. 2007

Clinical Cancer Research

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Purpose: Interaction of 17-allylamino-17-demethoxygeldanamycin (17-AAG) with heat shock protein 90 results in proteasomal degradation of many proteins, including Her-2-neu, with subsequent decreased expression of insulin-like growth factor binding protein-2 (IGFBP-2). Concentrations of both IGFBP-2 and Her-2 extracellular domain (Her-2 ECD) in sera of mice bearing BT474 human breast cancer xenografts decrease after 17-AAG treatment. We investigated whether this phenomenon occurred in patients. Materials and Methods: Eight to 15 plasma samples were obtained between 0 and 72 h from 27 patients treated with single-agent 17-AAG at doses between 10 and 307 mg/m 2 and 18 patients treated with 17-AAG at doses between 220 and 450 mg/m 2 combined with 70 to 75 mg/m 2 of docetaxel. Pretreatment plasma samples were also obtained from 12 healthy volunteers. Plasma IGFBP-2 and Her-2 ECD concentrations were quantitated by ELISA. Results: Pretreatment plasma IGFBP-2 concentrations in patients (171 F116 ng/mL) were 2-fold higher than those in healthy volunteers (85 F 44 ng/mL; P < 0.05). Following 17-AAG treatment, there were no consistent dose-dependent or time-dependent changes in plasma IGFBP-2 and Her-2 ECD concentrations. IGFBP-2 concentrations decreased by z40% in 8 patients, increased 2-to 5-fold in 8 patients, and remained essentially unchanged in 29 patients. Her-2 ECD concentrations decreased by z40% in 10 patients, increased 1.5-to 5-fold in 2 patients, and remained essentially unchanged in 25 patients. Conclusions: As previously reported, IGFBP-2 concentrations in plasma of cancer patients are significantly higher than those in healthy volunteers. In contrast to a mouse model, 17-AAG treatment was not consistently associated with decreases in IGFBP-2 or Her-2 ECD concentrations in patient plasma.

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Insulin-Like Growth Factor Binding Protein-2: Contributions of the C-Terminal Domain to Insulin-Like Growth Factor-1 Binding

Cited by 29 publications

References 39 publications

IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells

IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells

Leptin-regulated gene expression in MCF-7 breast cancer cells: mechanistic insights into leptin-regulated mammary tumor growth and progression

Evaluation of Plasma Insulin-like Growth Factor Binding Protein 2 and Her-2 Extracellular Domain as Biomarkers for 17-Allylamino-17-Demethoxygeldanamycin Treatment of Adult Patients with Advanced Solid Tumors

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