What is igf bp3

Test Code CPT Code s Not offered in Quest Infectious Disease Inc. Test Resources None found for this test Please visit our Clinical Education Center to stay informed on any future publications, webinars, or other education opportunities. Methodology Immunoassay IA. Service Area must be determined.

Preferred Specimen s 1 mL serum Minimum Volume 0. Preferred Specimen s 1 mL serum. IGFBP-3 gene has two vitamin D response elements one at and another at from the transcription start site Malinen et al. Upon the exposure of sense oligodeoxynucleotides along with vitamin D, as expected there was a decline in the cell proliferation and when the cells were incubated with antisense oligonucleotides along with vitamin D, the response was abrogated.

This interaction was reported to inhibit the triiodothyronine T3 responsive gene transcription. One of the novel partners identified amongst several was Rpb3. Rpb3 is required to recruit specific transcription factors that would initiate the process of transcription. Phosphorylated IGFBP-3 is required for the nuclear localization and for its interaction with the components within the nucleus. Epidermal growth factor receptor is RTK that is known to play an important role in the resistance to DNA-damaging radiation therapy and cytotoxic chemotherapy during cancer treatments.

Studies by Lin et al. Additionally, Lin et al. Apoptosis is an event that tips the balance towards cell death rather than survival and can be summarized as the programmed cell death. Apoptosis is mediated through two-cross linked pathways that involve either the cell surface receptors called the death receptors, activated by ligands or emanate from within the cell involving mitochondria, independent of ligands, commonly referred to as the extrinsic or the intrinsic apoptotic pathways, respectively Elmore, IGFBP-3 can function both as a suppressor of cell proliferation through the induction of apoptosis as well as in mediating cell proliferation.

Studies exhibiting the effects of human IGFBP-3, in vivo using transgenic mice show results contradictory to the in vitro studies using cell line. Serum and growth factor deprivation is also known to induce de novo synthesis of IGFBP-3 transcript as well as protein Grimberg et al.

Similar dose-dependent behavior has been observed with androgens, at low concentrations androgen are growth stimulating as they fail to induce IGFBP-3 expression Kojima et al.

There are several accumulating in vitro and in vivo evidences that support the anti-proliferative activity of IGFBP-3 is mediated through apoptosis in an IGF-independent manner Valentinis et al. Caveolin scaffolding domain not only binds with caveolin but also binds with protein kinase A PKA and consequently inactivates it Levin et al. IGFBP-3 was able to accentuate the ceramide-induced cell death, however, in the presence of fibronectin, it reversed the ceramide-induced cell death instead an increased cell survival was observed McCaig et al.

A study focused on understanding the phenomenon of germ cell apoptosis that occurs during spermatogenesis in males reported of the interaction between IGFBP-3 and BAX proteins using dot blot and co-immunoprecipitation. Together this interaction was seen to activate germ cell apoptosis via intrinsic apoptotic pathway involving mitochondria Jia et al.

Using yeast-two hybridisation system, humanin was found to be a binding partner of IGFBP-3 and was cloned in a study led by Cohen Ikonen et al.

A secretory protein in nature, humanin, is a 24 amino acid peptide involved in cell survival. Humanin has also been reported to interfere with BAX activation thus protecting against apoptosis Guo et al.

Humanin intereferes with the mitochondrial release of cytochrome c through preventing the translocation of BAX to mitochondria. Using yeast 2 hybrid system, E7 protein that is encoded by human papillomavirus type 16 was reported to interact with IGFBP-3 Mannhardt et al. Insulin-like growth factor binding protein-3 is the only known protein of all the IGFBPs to exhibit translocation from the nucleus into the cytoplasm. Following the secretion, IGFBP-3 is internalized into the cytoplasm and translocated into the nucleus, later detected in the cytoplasm suggestive of its ability to be exported from the nucleus into the cytoplasm.

Paharkova-Vatchkova, et al. This includes leucine-rich sequences that are analogous to HIV Rev and p Moreover, NES mutants also demonstrated a decrease in the oligonucleosomal fragmentation, which is indicative of apoptosis, clearly suggesting that the export of IGFBP-3 from the nucleus is required for the induction of apoptosis.

Using cell fractionation studies, IGFBP-3 has been reported to localize in the endoplasmic reticulum and the mitochondria. In the endoplasmic reticulum and mitochondria, IGFBP-3 could possibly play an essential role in triggering ER-stress, oncogene expression, death receptor ligation and oxidative stress induced apoptosis Paharkova-Vatchkova and Lee, Similar effect was observed in T47D, breast cancer cells stably transfected with IGFBP-3, where long-term cultures could induce cell growth, however, short-term cultures failed to induce growth Butt et al.

The increased growth was due to increased stimulation of EGFR signaling. The evidence to this is clear as IGFBP-3 has been demonstrated to be present in high levels in several cancers, including breast Valentinis et al.

As a matter of fact, in breast cancer there are reports indicating high expression of IGFBP-3 with poor prognosis and survival outcome Valentinis et al. On the contrary, in head and neck cancer Papadimitrakopoulou et al. One of the mechanisms explaining the ability of IGFBP-3 to potentiate breast cancer cell growth is the ability of IGFBP-3 to activate sphingosine kinase, an enzyme that incorporates phosphate group into sphingosine and the inhibition of sphingomyelinase, an enzyme that generates ceramide from sphingosine Figure 4.

Ceramide has been demonstrated to cause cell cycle arrest and apoptosis Perks et al. Sphingosine is a growth inhibitor, however, sphingosine1phosphate acts as a growth stimulator Granata et al. IGFBP-3 resulted in the increased doxorubicin-induced apoptosis due to increased ceramide levels in contrast to increased cell survival under serum deprived conditions due to decreased ceramide levels in HUVEC, endothelial cells Granata et al.

Sphingosine1phosphate is secreted following which it interacts with its receptor, Edg-3, that can transactivate EGFR in a metallomatrix protease-dependent manner Sukocheva et al.

It was also observed that silencing of shingosine1phosphate receptor1 and 3 could prevent the transactivation of EGFR but not sphingosine1phosphate receptor 2 Sukocheva et al. Figure 4. A IGFBP-3 potentiates cell survival through the inhibition of ceramide inducer of apoptosis synthesis by the inactivation of sphingomyelinase and B by the activation of sphingosine kinase that results in the formation of sphingosine 1 kinase from sphingosine.

While sphingosine can induce apoptosis, sphingosine 1 phosphate can potentiate cell survival. C Sphingosine 1 phosphate is secreted and can bind with its receptor, which can D transactivate EGFR, growth survival receptor. Further to the expansive role of IGFBP3 in eliciting both deleterious or protective effect, it plays an important role in ocular cells by conferring vascular protection to sites of injury by augmenting proliferation, migration, and differentiation of vascular progenitor cells.

Furthermore, research led by Maria Grant demonstrated that administration of IGFBP3 displayed a dose dependent reduction in artery constriction placed under intraluminal pressure. In breast cancer cells, IGFBP-3 was found to promote autophagy thereby augmenting cell survival during nutrition deprivation and hypoxia Grkovic et al.

The IGF-independent role of IGFBP-3 involving its association with the plasma membrane and its internalization into the cell and the nucleus, are important in regulating various important cellular functions.

The ability of mer peptides generated from the C -terminal domain of IGFBP-3 can specifically target cancer cells and it can be tagged with unrelated proteins or therapeutic drugs to efficiently transport within the cells, could prove to be an important biotechnological application of IGFBP-3 molecule.

Recent discoveries have identified IGFBP-3 to play dual function of a gate-keeper induction of apoptosis and cell cycle arrest as well as care-taker DNA repair through interaction with DNA-PK, induction of autophagy by interaction with GRP78 and the ability to regulate sphingolipids required for the cell survival pathways through mechanisms independent of IGFs.

The ability of IGFBP-3 to interact with several other proteins is a dynamic property exhibiting its multifaceted role in the modulating several critical cellular functions that are independent of IGFs and are context-dependent. Nuclear IGFBP-3 can function as a direct as well as indirect transcription factor and gene transcription, additionally, it also has a role to play in the process of DNA repair. The pleiotropic nature of IGFBP-3, whereby, it interacts with plethora of partners is an important property possessed by the molecule that has not only provided new insights into understanding the basic mechanisms of several cellular processes but could also play an essential role in deciphering the unknown complex mechanism s of IGFBP-3, thus establishing it as potential targets in several diseases including cancer and other metabolic diseases.

SV conceived, designed, and wrote the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Agostini-Dreyer, A. IGFBP-3 induced by ribotoxic stress traffics from the endoplasmic reticulum to the nucleus in mammary epithelial cells. Google Scholar.

Endocrinology , — Aishima, S. High expression of insulin-like growth factor binding protein-3 is correlated with lower portal invasion and better prognosis in human hepatocellular carcinoma. Cancer Sci. Alic, N. Stage debut for the elusive Drosophila insulin-like growth factor binding protein. Baumrucker, C. Baxter, R. Circulating binding proteins for the insulinlike growth factors. Trends Endocrinol. Bhattacharyya, N. Nonsecreted insulin-like growth factor binding protein-3 IGFBP-3 can induce apoptosis in human prostate cancer cells by IGF-independent mechanisms without being concentrated in the nucleus.

Boyle, B. Braulke, T. Type-2 IGF receptor: a multi-ligand binding protein. Immunohistochemical localization of insulin-like growth factor binding protein-1, -3 and -4 in human fetal tissues and their analysis in media from fetal tissue explants. Growth Regul. Butt, A. Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates pindependent radiation-induced apoptosis in human breast cancer cells. Insulin-like growth factor binding protein-3 expression is associated with growth stimulation of T47D human breast cancer cells: the role of altered epidermal growth factor signaling.

Campbell, P. Insulin-like growth factor-binding protein-3 binds fibrinogen and fibrin. Cerro, J. Chan, S. Inhibition of adipocyte differentiation by insulin-like growth factor-binding protein Chitnis, M. The type 1 insulin-like growth factor receptor pathway. Cancer Res. Chuang, S. Over expression of insulin-like growth factor binding protein 3 in clear cell renal cell carcinoma. Cleves, A. Protein transports: the nonclassical ins and outs.

Cobb, L. Enhancing the apoptotic potential of insulin-like growth factor-binding protein-3 in prostate cancer by modulation of CK2 phosphorylation. Cohen, P. Conover, C. Cell Mol. Durham, S. Elmore, S. Apoptosis: a review of programmed cell death.

Fagerholm, S. Rapid insulin-dependent endocytosis of the insulin receptor by caveolae in primary adipocytes. Fanayan, S. Signaling through the Smad pathway by insulin-like growth factor-binding protein-3 in breast cancer cells, Relationship to transforming growth factor-beta 1 signaling. Ferry, R. Cellular actions of insulin-like growth factor binding proteins.

Firth, S. Prog Growth Factor Res. Characterisation of recombinant glycosylation variants of insulin-like growth factor binding protein Cellular actions of the insulin-like growth factor binding proteins. Development of resistance to insulin-like growth factor binding protein-3 in transfected T47D breast cancer cells. Structural determinants of ligand and cell surface binding of insulin-like growth factor-binding protein Fontana, J.

Retinoid modulation of insulin-like growth factor-binding proteins and inhibition of breast carcinoma proliferation.

Forbes, B. Insulin-like growth factor binding proteins: a structural perspective. Lausanne Fowlkes, J. Characterization of glycosaminoglycan-binding domains present in insulin-like growth factor-binding protein Freitas, N. Mechanisms and signals for the nuclear import of proteins. Genomics 10, — Frystyk, J. Developmental changes in serum levels of free and total insulin-like growth factor I IGF-I , IGF-binding protein-1 and -3, and the acid-labile subunit in rats. Fuchs, S. Pathway for polyarginine entry into mammalian cells.

Biochemistry 43, — Gill, Z. Girnita, L. Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor IGF-1R signaling regulation. Sci 71, — Goda, N. Intracellular protein delivery activity of peptides derived from insulin-like growth factor binding proteins 3 and 5. Cell Res. Goltz, J. A role for microtubules in sorting endocytic vesicles in rat hepatocytes.

Granata, R. Dual effects of IGFBP-3 on endothelial cell apoptosis and survival: involvement of the sphingolipid signaling pathways. Grimberg, A. IGFBP-3 mediates pinduced apoptosis during serum starvation. Grkovic, S. Oncogene 32, — Gui, Y. Guo, B. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature , — Habault, J. Recent advances in cell penetrating peptide-based anticancer therapies.

Molecules Han, V. Spatial and temporal patterns of expression of messenger RNA for insulin-like growth factors and their binding proteins in the placenta of man and laboratory animals. Placenta 21, — IGF-binding protein mRNAs in the human fetus: tissue and cellular distribution of developmental expression.

Hodgkinson, S. Metabolic clearance of insulin-like growth factor-II in sheep. Honegger, B. Imp-L2, a putative homolog of vertebrate IGF-binding protein 7, counteracts insulin signaling in Drosophila and is essential for starvation resistance. Most GH resistance in childhood is mild to moderate, with causes ranging from poor nutrition to severe systemic illness eg, renal failure. Severe childhood GH resistance is rare and usually due to GH-receptor defects. The prevalence and causes of adult GH resistance are uncertain, but adult GH deficiency is seen mainly in pituitary tumor patients.

It is associated with decreased muscle bulk and increased cardiovascular morbidity and mortality, but replacement therapy remains controversial. Endogenous GH excess is caused mostly by GH-secreting pituitary adenomas, resulting in gigantism, if acquired before epiphyseal closure, and in acromegaly thereafter.

Both conditions are associated with generalized organomegaly, hypertension, diabetes, cardiomyopathy, osteoarthritis, compression neuropathies, a mild increase in cancer risk, and diminished longevity.

It is plausible, but unproven, that long-term rhGH-overtreatment may result in similar adverse outcomes. For all applications, insulin-like growth factor 1 IGF-1 measurement has generally been shown to have superior diagnostic sensitivity and specificity compared with insulin-like growth factor-binding protein 3 IGFBP The combination of IGF-1 and IGFBP-3 measurements appears superior to determining either analyte alone in the diagnosis of growth hormone GH deficiency and resistance, and in the monitoring of recombinant human GH therapy.

In GH deficiency, GH levels are also low and show suboptimal responses in stimulation tests eg, exercise, clonidine, arginine, ghrelin, growth hormone-releasing hormone, insulin-induced hypoglycemia , while in severe GH resistance, GH levels are substantially elevated.

However, dynamic GH testing is not always necessary for diagnosis. If it is undertaken, it should be performed and interpreted in endocrine testing centers under the supervision of an endocrinologist. Higher levels are rarely associated with any further therapeutic gains but could potentially lead to long-term problems of GH excess.

In successfully treated patients, both levels should be within the normal range, ideally within the lower third. Clin Chem. Wetterau L, Cohen P: Role of insulin-like growth factor monitoring in optimizing growth hormone therapy.