Molecular Distribution of IGF Binding Protein-5 in Human Serum

Baxter, Robert C.; Meka, S; Firth, Sue M.

doi:10.1210/jcem.87.1.8151

Cited by 35 publications

(11 citation statements)

References 31 publications

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“…3A, bottom panel, lane 2). As noted previously (16), the relative intensity of the IGFBP-3 bands is reduced in these mice, probably because IGFBP-5 may sequester IGF-I from IGFBP-3, leading to accelerated degradation of IGFBP-3 (7). In marked contrast to this pattern, no band equivalent to wtBP5-myc was observed in the ligand blot for any of the lines that expressed mutBP5-myc (Fig.…”

Section: Derivation Of Lines Overexpressing Mutbp5supporting

confidence: 64%

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IGF‐independent effects of insulin‐like growth factor binding protein‐5 (Igfbp5) in vivo

et al. 2009

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IGF activity is regulated tightly by a family of IGF binding proteins (IGFBPs). IGFBP-5 is the most conserved of these and is up-regulated significantly during differentiation of several key lineages and in some cancers. The function of IGFBP-5 in these physiological and pathological situations is unclear, however, several IGFBP-5 sequence motifs and studies in vitro suggest IGF-independent actions. Therefore, we aimed to compare the phenotypes of mice overexpressing wild-type Igfbp5 or an N-terminal mutant Igfbp5 with negligible IGF binding affinity. Both significantly inhibited growth, even at low expression levels. Even though wild-type IGFBP-5 severely disrupted the IGF axis, we found no evidence for interaction of mutant IGFBP-5 with the IGF system. Further, overexpression of wild-type IGFBP-5 rescued the lethal phenotype induced by "excess" IGF-II in type 2 receptor-null mice; mutant IGFBP-5 overexpression could not. Therefore, wild-type IGFBP-5 provides a very effective mechanism for the inhibition of IGF activity and a powerful in vivo mechanism to inhibit IGF activity in pathologies such as cancer. This study is also the first to suggest significant IGF-independent actions for IGFBP-5 during development.

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Section: Derivation Of Lines Overexpressing Mutbp5supporting

confidence: 64%

“…IGFBP-5 is the most conserved of the IGFBPs, present in all vertebrates. Like IGFBP-3, IGFBP-5 can form a complex that is retained in serum and maintains a latent reservoir of IGFs (7). IGFBP-5 is expressed early in embryonic development; its message levels are abundant in somites, indicating a potential function in myogenesis (8).…”

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confidence: 99%

IGF‐independent effects of insulin‐like growth factor binding protein‐5 (Igfbp5) in vivo

et al. 2009

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“…Resolved proteins were transferred to nitrocellulose membranes and probed with anti-Bax polyclonal (1:1000 dilution; BD Pharmingen), anti-Bcl-2 monoclonal (0.8 g/ml; Dako, Carpinteria, CA), or chicken anti-human IGFBP-5 (1:100; Ref. 29) antibodies overnight at 4°C. This was followed by incubation with anti-rabbit (for Bax, 1:10,000 dilution) or anti-mouse (for Bcl-2, 1:2000 dilution) IgG conjugated with horseradish peroxidase.…”

Section: Methodsmentioning

confidence: 99%

“…IGFBP-5 fragments eluted at 26 -27 min, and intact IGFBP-5 at 30 -32 min. Concentrations of IGFBP-5 in CM from IGFBP-5 expressing cells were quantitated by IGFBP-5-specific radioimmunoassay as previously described (29).…”

Section: Analysis Of Igfbp-5 In Conditioned Media-mda-mb-231mentioning

confidence: 99%

Insulin-like Growth Factor-binding Protein-5 Inhibits the Growth of Human Breast Cancer Cells in Vitro and in Vivo

Butt

Dickson

McDougall

et al. 2003

Journal of Biological Chemistry

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131

125

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The role of insulin-like growth factor-binding protein (IGFBP)-5 in human breast cancer cell growth is unclear. We determined the effects of IGFBP-5 expression on the growth of human breast cancer cell lines in vivo and in vitro. Expression of IGFBP-5, both by stable transfection and adenoviral-mediated infection, was inhibitory to the growth of MDA-MB-231 and Hs578T human breast cancer cells over a 13-day period. IGFBP-5 expression resulted in a G 2 /M cell cycle arrest and the induction of apoptosis in both cell lines, an effect that was abrogated in the presence of the broad-spectrum caspase inhibitor, z-VAD-fmk. IGFBP-5-induced apoptosis was associated with a transcriptional increase in expression of the proapoptotic regulator bax and decrease in the anti-apoptotic bcl-2 compared with vector controls. Secreted IGFBP-5 when added exogenously to breast cancer cells was not internalized and had no effect on cell growth or apoptosis, suggesting that IGFBP-5 may elicit its inhibitory effects via a novel, intracrine mechanism. In athymic nude mice, stable expression of IGFBP-5 significantly inhibited both the formation and growth of tumors derived from MDA-MB-231 cells. IGFBP-5-expressing tumors also had a significantly elevated level of bax mRNA and decreased levels of bcl-2 mRNA compared with vector tumors. These data suggest that IGFBP-5 is a potent growth inhibitor and proapoptotic agent in human breast cancer cells via modulation of cell cycle regulation and apoptotic mediators.The insulin-like growth factor-binding proteins (IGFBPs) 1 are a family of proteins that bind with high affinity to IGFs and modulate their mitogenic actions by regulating their ability to interact with their signaling receptor, the type I IGF receptor (IGFRI, reviewed in Ref. 1). However, it is now becoming clear that many IGFBPs have direct roles in the regulation of cell growth and cell death. For example, we and others have demonstrated the antiproliferative and proapoptotic effects of IGFBP-3 in breast (2-4) and prostate (4) cancer cell lines.The role of IGFBP-5 in cell growth is complex, with reports that it can either stimulate or inhibit cell proliferation in various experimental systems (5-7). There is also evidence that IGFBP-5 expression is up-regulated by antiproliferative agents such as retinoic acid (8), vitamin D-related compounds (9), and antiestrogen ICI 182780 (10), with some evidence that it may mediate their growth inhibitory effects (8, 10). Similarly, growth stimulation of human breast cancer cells by estradiol is associated with a down-regulation of IGFBP-5 expression (10), although exogenous IGFBP-5 had no effect on IGF-I-stimulated DNA synthesis in the breast cancer cell line, MCF-7 (11). They demonstrated that addition of exogenous IGFBP-5 to Hs578T cells protects these cells from ceramide-induced apoptosis, suggesting IGFBP-5 may have a survival function in response to apoptotic stimuli (20,21). A similar conclusion was reached by Roschier et al. (22) following their demonstration that induction of apoptosis...

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“…It was surprising, therefore, that the proportion of free IGF-I in serum tended to increase in Igfbp5-overexpressing mice, although this also occurred in the growth-retarded liver Igf1 and Als double-null mice (25). The proportion of different IGFBPs in serum is also important, and, in this regard, IGFBP-5 can effectively compete with IGFBP-3 for serum ternary complex formation with the acid-labile subunit in vivo (38). The demonstration of IGFBP-5-myc protein at an appropriate M r for ternary complex formation suggests that IGFBP-5 could have displaced IGFBP-3 from this complex, retaining circulating IGF in a relatively tightly bound ternary complex (39).…”

Section: Igf-independent Actions Of Igfbp-5mentioning

confidence: 99%

Insulin-like growth factor-binding protein 5 ( Igfbp5 ) compromises survival, growth, muscle development, and fertility in mice

Salih

Tripathi

Holding

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

159

123

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The insulin-like growth factors (IGFs) are essential for development; bioavailable IGF is tightly regulated by six related IGF-binding proteins (IGFBPs). Igfbp5 is the most conserved and is developmentally up-regulated in key lineages and pathologies; in vitro studies suggest that IGFBP-5 functions independently of IGF interaction. Genetic ablation of individual Igfbps has yielded limited phenotypes because of substantial compensation by remaining family members. Therefore, to reveal Igfbp5 actions in vivo, we generated lines of transgenic mice that ubiquitously overexpressed Igfbp5 from early development. Significantly increased neonatal mortality, reduced female fertility, whole-body growth inhibition, and retarded muscle development were observed in Igfbp5-overexpressing mice. The magnitude of the response in individual transgenic lines was positively correlated with Igfbp5 expression. Circulating IGFBP-5 concentrations increased a maximum of only 4-fold, total and free IGF-I concentrations increased up to 2-fold, and IGFBP-5 was detected in high Mr complexes; however, no detectable decrease in the proportion of free IGF-I was observed. Thus, despite only modest changes in IGF and IGFBP concentrations, the Igfbp5-overexpressing mice displayed a phenotype more extreme than that observed for other Igfbp genetic models. Although growth retardation was obvious prenatally, maximal inhibition occurred postnatally before the onset of growth hormone-dependent growth, regardless of Igfbp5 expression level, revealing a period of sensitivity to IGFBP-5 during this important stage of tissue programming.T he insulin-like growth factors (IGF-I and -II) are essential for growth and development (1). Six high-affinity IGF-binding proteins (IGFBP-1 to IGFBP-6; refs. 2 and 3) strictly orchestrate IGF action. Despite their considerable sequence homology, each exhibits a discrete expression pattern and possesses an individual subset of motifs, signifying that although IGFBPs have common actions, they may also have unique properties.IGFBP-5 is the most conserved of the IGFBPs (4) and has been highlighted as a focal regulatory factor during the development of several key cell lineages, e.g., myoblasts (5) and neural cells (6, 7). In mice, Igfbp5 is expressed in the embryo from early development, principally in the myotomal component of the somites and developing central nervous system (8). Postnatally, serum IGFBP-5, in common with IGFBP-3, forms a ternary complex with IGF-I or IGF-II and the acid-labile subunit (9). Igfbp5 is up-regulated in the aggressive pediatric cancer, rhabdomyosarcoma (10), in the progression of prostate cancers to androgen independence (11), and in smooth muscle-derived uterine leiomyoma (12), indicating a function in neoplasia.IGFBP-5 initially binds IGFs with high affinity, principally by an N-terminal motif (13), and inhibits IGF activity by preventing IGF interaction with the type 1 receptor. It is further subject to regulated posttranslational modifications (3) to induce conformational changes that dec...

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Molecular Distribution of IGF Binding Protein-5 in Human Serum

Cited by 35 publications

References 31 publications

IGF‐independent effects of insulin‐like growth factor binding protein‐5 (Igfbp5) in vivo

IGF‐independent effects of insulin‐like growth factor binding protein‐5 (Igfbp5) in vivo

Insulin-like Growth Factor-binding Protein-5 Inhibits the Growth of Human Breast Cancer Cells in Vitro and in Vivo

Insulin-like growth factor-binding protein 5 ( Igfbp5 ) compromises survival, growth, muscle development, and fertility in mice

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