Transferrin is a glycoprotein with an approximate molecular weight of 76,500, most of which is contributed by a polypeptide chain of 679 amino acid residues. Transferrin is the product of an ancient intragenic duplication that led to homologous carboxyl and amino domains, each of which binds 1 ion of ferric iron. Transferrin carries iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body. It carries iron into cells by receptor-mediated endocytosis. Iron is dissociated from transferrin in a nonlysosomal acidic compartment of the cell. Provision of intracellular iron for synthesis of ribonucleotide reductase, an enzyme that catalyzes the first step leading to DNA synthesis, is required for cell division. After dissociation of iron, transferrin and its receptor return undegraded to the extracellular environment and the cell membrane, respectively. Yang et al. (1994) reported the isolated of human transferrin cDNA, its characterization and the chromosomal localization of its gene.
NCBI Summary:
The protein encoded by this gene is a glycoprotein with an approximate molecular weight of 76.5 kDa. It is thought to have been created as a result of an ancient gene duplication event that led to generation of homologous C and N-terminal domains each of which binds 1 ion of ferric iron. The function of this encoded protein is to transport iron from the intestine, reticuloendothelial system, and liver parenchymal cells to all proliferating cells in the body. In addition to its function in iron transport, this protein may also have a physiologic role as granulocyte/pollen-binding protein (GPBP) involved in the removal of certain organic matter/allergins from serum.
General function
Cell death/survival, DNA Replication, Metabolism
Comment
Proliferating cells have an absolute requirement for iron, which is delivered by transferrin with subsequent intracellular transport via the transferrin receptor.
Effects of transferrin on aromatase activity in porcine granulosa cells in vitro. Durlej M et al. Proliferating cells have an absolute requirement for iron, which is delivered by transferrin with subsequent intracellular transport via the transferrin receptor. Recent studies have reported that transferrin plays a crucial role in the local regulation of ovarian function, apart from its iron-binding characteristic. Therefore, the present study was undertaken to explore the possible role of transferrin in porcine granulosa cells function by examining its influence on aromatase activity, the most important indicator of follicular cell differentiation. In the first series of studies, pig granulosa cells isolated from small, immature follicles were cultured in the presence of transferrin alone (10 microg/ml or 100 microg/ml) or with the addition of FSH (100ng/ml). The second series of studies was undertaken to determine transferrin-stimulated granulosa cells ability to aromatize exogenous testosterone (1x10(-7)M). One hour after the establishment of cultures an aromatase inhibitor CGS16949A was added to test its influence on estradiol production. After 48 hours, cultures were terminated and cells were processed for immunocytochemical staining of aromatase. Media were frozen for further estradiol level analysis. Positive immunostaining for aromatase was found in all granulosa cell cultures. The intensity of immunostaining was always stronger in cultures supplemented with FSH whereas the addition of transferrin had no effect. Granulosa cells in vitro synthesized the highest amount of estradiol after the addition of FSH and exogenous testosterone as measured radioimmunologically. Concomitant treatment with FSH and transferrin caused an inhibition of FSH-stimulated aromatase activity. The production of estradiol also declined in the presence of FSH, testosterone and transferrin. This study demonstrates that transferrin had a dose-dependent inhibitory effect on FSH-stimulated aromatase activity, which was confirmed by radioimmunoassay. Our results indicate that transferrin may be an important factor in the regulation of granulosa cell diferentiation.
Serum-free media for cultured granulosa cells and follicles are routinely, supplemented with insulin, transferrin , and selenium (for example see Barano et al.(1985); Eppig et al.(1998). Yu et al. (1991) reported an inhibitory effect of transferrin on differentiation of rat granulosa cells in vitro. They indicated that 1) transferrin may be an important negative modulator of the stimulatory actions of FSH or IGF-I and other factors acting on granulosa cells; 2) the inhibitory effects of transferrin require the presence of FSH or other factors such as IGF-I or insulin, which facilitate granulosa cell differentiation; and 3) different mechanisms are involved in the modulating effects of transferrin on inhibin and progesterone production. In cultured rat granulosa cells, Li et al. (1991) reported that coincubation with increasing doses of transferrin produced a dose-dependent inhibition of FSH-stimulated aromatase activity. Kawano et al.(1995) reported that progesterone production by porcine granulosa cells was suppressed by transferrin in the presence of FSH.
Entman et al. (1987) reported transferrin-like protein present in the follicular fluid of stimulated ovarian cycles. The transferrin concentration correlates with the follicular morphologic maturity and steroidogenesis, varies among follicles, and often exceeds serum concentrations. An intermediate range of transferrin concentration is associated with the highest likelihood of oocyte fertilization in vitro. The biological significance of these observations may relate to an optimum degree of follicle maturation. Because iron and transferrin concentration increase in follicular fluid with advancing follicular maturation, Aleshire et al studied the distribution of transferrin and its receptor in rat and human granulosa cells with light and electron microscopic immunohistochemistry. Intense cytoplasmic staining was found in granulosa cells, with immunostaining enhancement occurring with advanced follicle maturation, including the periovulatory period. Immunoelectron microscopy showed transferrin throughout the cytoplasm, often in proximity to polyribosomes and vesicular structures. When transferrin was absent in the culture medium used to maintain granulosa cells, diminished transferrin immunostaining was seen. Based on these findings, the authors conclude that follicular maturation is closely related to high levels of cellular transferrin and transferrin receptor. Aleshire et al.(1989) proposed that acquisition of transferrin occurs primarily by either ultrafiltration or facilitated diffusion, whereas de novo local synthesis does not have a major role.
Follicle stages
Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum
Comment
Briggs et al undertook immunocytochemical studies which revealed that transferrin and its receptor are distributed heterogeneously in human granulosa cells, with more pronounced expression in more mature follicles. Expression within the oocyte itself was not prominent until the antral stage of development. Using nested reverse trancription-polymerase chain reaction (RT-PCR), transferrin mRNA expression was demonstrated in granulosa cells of the human and mouse ovary but not in the oocyte.