Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients

Insulin-like growth factor (IGF) signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM). In the extracellular environment, the majority of IGF molecules are bound to one of six IGF-binding proteins (IGFBP1-6), leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17), monoclonal gammopathy of undetermined significance (MGUS) (n = 37), and control individuals (n = 15), using ELISA (IGFs) and 125I-IGF1 Western Ligand Blotting (IGFBPs). MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5-3.8 fold) and decrease in intact IGFBP-3 (0.6-0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration

The Insulin-Like Growth Factor System in the Long-Lived Naked Mole-Rat.

Naked mole-rats (Heterocephalus glaber) (NMRs) are the longest living rodents known. They show negligible senescence, and are resistant to cancers and certain damaging effects associated with aging. The insulin-like growth factors (IGFs) have pluripotent actions, influencing growth processes in virtually every system of the body. They are established contributors to the aging process, confirmed by the demonstration that decreased IGF signaling results in life-extending effects in a variety of species. The IGFs are likewise involved in progression of cancers by mediating survival signals in malignant cells. This report presents a full characterization of the IGF system in the NMR: ligands, receptors, IGF binding proteins (IGFBPs), and IGFBP proteases. A particular emphasis was placed on the IGFBP protease, pregnancy-associated plasma protein-A (PAPP-A), shown to be an important lifespan modulator in mice. Comparisons of IGF-related genes in the NMR with human and murine sequences indicated no major differences in essential parts of the IGF system, including PAPP-A. The protease was shown to possess an intact active site despite the report of a contradictory genome sequence. Furthermore, PAPP-A was expressed and translated in NMRs cells and retained IGF-dependent proteolytic activity towards IGFBP-4 and IGF-independent activity towards IGFBP-5. However, experimental data suggest differential regulatory mechanisms for PAPP-A expression in NMRs than those described in humans and mice. This overall description of the IGF system in the NMR represents an initial step towards elucidating the complex molecular mechanisms underlying longevity, and how these animals have evolved to ensure a delayed and healthy aging process

A study of the women in W. S. Gilbert\u27s Patience , Iolanthe , and Princess Ida ; or, the folly of being feminist.

In his three operas of the early 1880s--Patience, Iolanthe, and Princess Ida--W. S. Gilbert directs his wit at free-thinking women. Although the overt subjects of these operas (Aestheticism, the reform of the House of Lords, and women\u27s education) have received much critical attention, the subplot--the conflict between men and women--has not. In all three, the tension in the plot is the result of the sexual struggle; and, in all three, Gilbert trivializes the feminist idea of woman\u27s independence and advocates the Separate Spheres theory, which postulated that equality between the sexes was not possible because of the God-ordained biological difference between men and women. The unwritten natural laws of Victorian society, based on these sexual differences, were reinforced by written laws which upheld men\u27s natural superiority by removing from women, through marriage, any control they had over their possessions, their children, and their lives. In these operas, Gilbert punishes those women who transgress the natural laws. The women--the heroines and the dames, in particular, but also the female choruses--are corrected by the male-controlled society and safely married off by the end of the operas. In Patience, the women are controlled by love--either artificial, aesthetic love or sincere and practical love; womanly women are paired with manly men, and the asexual Bunthorne is left without a mate. The power of love almost destroys the Separate Spheres in Iolanthe, causing chaos as the women invade the masculine world of law and politics. However, not even love can overcome the natural differences, and the fairy and mortal worlds are separate once again at the conclusion of the opera. In Princess Ida, the women try to overcome the natural differences through education, but they are defeated in their war with the men by their biological duty to provide posterity. Gilbert\u27s advocacy of the Separate Spheres theory pleased his conservative audience; it also dates these three Woman Question operas more than the overt satire he aimed at the Victorian concerns of Aestheticism, political reform, and women\u27s education

Heparin binding mechanism of the insulin-like growth factor (IGF) 2 / IGF binding protein 2 complex

IGF1 and IGF2 are potent stimulators of diverse cellular activities such as differentiation and mitosis. Six IGF-binding proteins (IGFBP1–IGFBP6) are primary regulators of IGF half-life and receptor availability. Generally, the binding of IGFBPs inhibits IGF receptor activation. However, it has been shown that IGFBP2 in complex with IGF2 (IGF2/IGFBP2) stimulates osteoblast functionin vitroand increases skeletal massin vivo. IGF2 binding to IGFBP2 greatly increases the affinity for 2- or 3-carbonO-sulfated glycosaminoglycans (GAGs), e.g. heparin and heparan sulfate, which is hypothesized to preferentially and specifically target the IGF2/IGFBP2 complex to the bone matrix. In order to obtain a more detailed understanding of the interactions between the IGF2/IGFBP2 complex and GAGs, we investigated heparin-binding properties of IGFBP2 and the IGF2/IGFBP2 complex in a quantitative manner. For this study, we mutated key positively charged residues within the two heparin-binding domains (HBDs) in IGFBP2 and in one potential HBD in IGF2. Using heparin affinity chromatography, we demonstrate that the two IGFBP2 HBDs contribute differentially to GAG binding in free IGFBP2 and the IGF2/IGFBP2 protein complex. Moreover, we identify a significant contribution from the HBD in IGF2 to the increased IGF2/IGFBP2 heparin affinity. Using molecular modeling, we present a novel model for the IGF2/IGFBP2 interaction with heparin where all three proposed HBDs constitute a positively charged and surface-exposed area that would serve to promote the increased heparin affinity of the complex compared with free intact IGFBP2.</jats:p