In vivo, insulin-like growth factors I (147440) and II (147470) are always complexed to one of a family of 6 IGF-binding
proteins. . In juvenile and adult mammals, 80% to 85% of serum IGFs are found in a ternary
complex of 150 kD composed of 1 molecule each of IGF, IGFBP3, and a protein that is found only in serum, the acid-labile
subunit (ALS).
NCBI Summary:
This gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein forms a ternary complex with insulin-like growth factor acid-labile subunit (IGFALS) and either insulin-like growth factor (IGF) I or II. In this form, it circulates in the plasma, prolonging the half-life of IGFs and altering their interaction with cell surface receptors. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
General function
Extracellular binding protein
Comment
Cellular localization
Secreted
Comment
IGF-binding protein-3-induced growth inhibition and apoptosis do not require cell surface binding and nuclear translocation in human breast cancer cells.
Baxter et al .////////////Alterations in the sensitivity of serum insulin-like growth factor 1 and insulin-like growth factor binding protein-3 to octreotide in polycystic ovary syndrome. Morris RS et al. (1995) To determine if the somatostatin analog, octreotide, affects insulin and related peptides and, hence, androgen levels differently between polycystic ovary syndrome (PCOS) patients and controls. Prospective controlled trial. Reproductive endocrinology clinic of our medical center. Eleven women with PCOS and six matched ovulatory controls. Octreotide (100 micrograms) was administered subcutaneously in the midfollicular phase. Serum was obtained before and at 60, 120, 180, and 240 minutes after octreotide. Fasting insulin, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), T, androstenedione (A), and LH. In PCOS, baseline levels of T, A, LH, and fasting insulin were significantly higher than in controls. Pretreatment IGF-1 and IGFBP-3 levels were similar in PCOS and controls. Octreotide reduced fasting insulin levels significantly but to a similar degree in control and PCOS patients (77% and 90%, respectively). Both groups also experienced a significant decrease in LH levels after octreotide administration, but no significant changes were demonstrated in serum T or A. However, serum IGF-1 suppression in PCOS was greater (63% versus 8% in controls). Serum IGFBP-3 levels increased after octreotide administration in both groups with a larger increase (40%) occurring in the PCOS patients. These data suggest that women with PCOS may be more sensitive to the effects of octreotide in decreasing IGF-1 and increasing IGFBP-3. Although no significant changes could be demonstrated in ovarian androgens after a single dose, octreotide effectively reduced serum LH and insulin and, as such, may prove useful in treating some patients with PCOS.//////////////////
Ovarian function
Follicle development, Follicle atresia, Oogenesis
Comment
Wandji SA, et al 2000 reported that porcine ovarian cells express messenger ribonucleic acids for the acid-labile subunit (ALS) and insulin-like
growth factor binding protein-3 during follicular and luteal phases of the estrous cycle. These transcripts were colocalized with aromatase mRNA, a marker
of healthy granulosa cells. IGFBP-3 mRNA was equally expressed in granulosa cells of all growing follicles. In contrast,
granulosa cell ALS mRNA levels were higher in preantral and small antral follicles than in large antral follicles.
In thecal cells, expression of mRNA for IGFBP-3, ALS and cyclin D1 (a marker of cell proliferation) was restricted to
healthy (aromatase-expressing) follicles. In those follicles, thecal expression of IGFBP-3 mRNA was low or absent in
preantral follicles but increased (P < 0.05) in antral follicles. Thecal cell ALS transcripts peaked in small antral follicles (P
< 0.05) and then declined. In granulosa cells of atretic follicles, transcripts for aromatase were greatly reduced, whereas
IGFBP-3 mRNA levels remained high. In contrast, ALS transcript levels were greatly reduced in both granulosa and thecal cells of atretic follicles. After ovulation, IGFBP-3 mRNA was moderately expressed in granulosa
luteins but strongly detected in a few theca-derived cells and in vascular endothelial cells. This study demonstrates that
follicular fluid IGFBP-3 and ALS, like the IGFs, originate (at least in part) from the ovary. The ability of follicular cells to
synthesize, assemble, and store all components of the ternary complex may be critical in determining the bioavailability of
follicular IGF-I and -II. izhar
Expression regulated by
FSH
Comment
Insulin-like growth factor-binding protein-3 in porcine ovarian granulosa cells: gene cloning, promoter mapping, and follicle-stimulating hormone regulation.
Ongeri EM,et al .
The role and regulation of IGF-binding protein-3 (IGFBP-3) in the ovary is not fully understood. We cloned and determined the sequence of 12,257 bp of the pig IGFBP-3 gene that includes 4,296 bp of the flanking promoter sequence. The porcine IGFBP-3 promoter sequence shares two highly conserved regions with the human and bovine IGFBP-3 promoters and a mouse DNA clone. The first is a 38 bp region between -1095 and -1058, whereas the second is a 73-bp region between -63 and +10 of the pig sequence. Projected translation of the open reading frame of our sequence gave a peptide sequence identical to that determined by peptide sequencing, but with 27 additional amino acids upstream of this sequence and is highly similar to the human, bovine, rat, and mouse IGFBP-3 peptides. Using RT-PCR we demonstrated that FSH regulates IGFBP-3 mRNA expression in a biphasic manner, with an early induction (maximal at 3 h) and an inhibition at 24 h after FSH treatment. The inhibition at 24 h was not due to changes in IGFBP-3 mRNA stability. A similar pattern of FSH modulation of the IGFBP-3 gene transcription was demonstrated by the reporter activity of granulosa cells transiently transfected with IGFBP-3 promoter constructs. The site for FSH stimulation of the IGFBP-3 gene was localized to the sequence between -61 and -48 relative to the transcription start site. Regulation of IGFBP-3 transcription by FSH suggests a role for IGFBP-3 in follicular development that may be independent of IGF-I.
Ovarian localization
Oocyte, Granulosa, Theca, Luteal cells
Comment
Arraztoa JA, et al 2002
analyzed IGFBP mRNA expression patterns in ovaries from mid-cycle rhesus monkeys using in situ hybridization. IGFBP-1 mRNA was concentrated in theca-interstitial cells and was present at low levels in granulosa cells of atretic follicles. IGFBP-2 mRNA was expressed in the ovarian surface epithelium and granulosa cells of all antral follicles, including obviously atretic as well as dominant follicles. IGFBP-3 mRNA was localized in oocytes and in the ovarian vascular endothelium; this mRNA was also concentrated in the superficial cortical stroma in which it was distinctly more abundant in the nondominant ovary. Granulosa cells of mature dominant and ovulatory follicles selectively expressed IGFBP-5 mRNA. IGFBP-5 mRNA was also widely expressed in the ovarian stroma, in which, in contrast to IGFBP-3, it was distinctly more abundant in dominant, compared with nondominant, ovary. IGFBP-6 mRNA was present at low levels in the ovary interstitium and theca externa and was more abundant in the ovary surface epithelium. These novel data reveal distinctive cellular expression patterns for IGFBPs 1, 2, 3, 5, and 6 in the nonhuman primate ovary, suggesting distinct roles for each binding protein in ovarian function.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Influence of insulin-like growth factor-binding proteins-2 and -3 in the pathogenesis of cystic ovarian disease in cattle. Rodrguez FM et al. Ovarian cysts are one of the major causes of infertility in dairy cows. The development is associated with an endocrine imbalance in the hypothalamo-hypophyseal-gonadal axis in which endocrine factors participate in follicular growth and differentiation and in the secretion of ovarian hormones. Insulin-like growth factor family are essential local regulators of ovarian follicle development and functionality and actions are mediated by binding protein activity. The aim of the present study was to analyze the expression of IGFBP-2 and IGFBP-3 in developing follicles of normal estrous cycling animals and with spontaneous and induced cystic ovarian disease (COD) to determine IGF bioavailability. The mRNA of IGFBP-2 and IGFBP-3 in follicular walls was quantified by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. Protein expression was analyzed by immunohistochemistry. The results demonstrated reduced amounts of mRNA of both IGFBPs in the granulosa cells of ovarian follicles of animals with COD (P<0.05). The present study suggests that the IGF system or imbalances between IGFs and IGFBPs may be involved in COD of cattle.