Cyclic‐glycine‐proline accelerates mammary involution by promoting apoptosis and inhibiting IGF‐1 function

Abstract

In rodents, post-lactational involution of mammary glands is characterized by the loss of mammary epithelial cells via apoptosis, which is associated with a decline in the expression of insulin-like growth factor-1 (IGF-1). Overexpression of IGF-1 delays involution by inhibiting apoptosis of epithelial cells and preserving the remaining secretory alveoli. Cyclic-glycine-proline (cGP), a metabolite of IGF-1, normalizes IGF-1 function under pathological conditions by regulating the bioavailability of IGF-1. The present study investigated the effect of cGP on the physiological decline in IGF-1 function during post-lactational mammary involution. Rat dams were gavaged with either cGP (3 mg/kg) or saline once per day from post-natal d8-22. Before collecting tissue on post-natal d23, a pair of mammary glands were sealed on d20 (72 hr-engorgement, thus representative of late-involution) and d22 (24 hr-engorgement, thus representative of mid-involution), while the remaining glands were allowed to involute naturally (early-involution). During early-involution, cGP accelerated the loss of mammary cells through apoptosis, resulting in an earlier clearance of intact secretory alveoli compared with the control group. This coincided with an earlier up-regulation of the cell survival factors, Bcl-xl and IGF-1R, in the early-involution cGP glands compared with the control glands. During late-involution, cGP reduced the bioactivity of IGF-1, which was evident through decreased phosphorylation of IGF-1R in the regressed alveoli. Maternal administration of cGP did not alter milk production and composition during early-, peak-, or late-stage of lactation. These data show that cGP accelerates post-lactational involution by promoting apoptosis and the physiological decline in IGF-1 function.

Supplementation of Blackcurrant Anthocyanins Increased Cyclic Glycine-Proline in the Cerebrospinal Fluid of Parkinson Patients: Potential Treatment to Improve Insulin-Like Growth Factor-1 Function

“…The deficiency of IGF-1 could be the result of impaired autocrine regulation trough interacting with IGFBPs [ 8 ]. We have reported the role of cGP in regulating IGF-1 bioavailability by competing with IGF-1 binding to IGFBP-3 [ 15 ] under both physiological [ 9 , 29 ] and pathological conditions [ 8 ]. The competitive binding between IGF-1 and cGP is concentration-dependent, resulting in more cGP and more active IGF-1.…”

Cyclo‐glycylproline attenuates hydrogen peroxide‐induced cellular damage mediated by the MDM2‐p53 pathway in human neural stem cells

“…This is the first study to reveal the molecular mechanism underlying cGP‐induced neuroprotective properties in a model of brain damage. cGP can bind to IGFBP‐3 and modulate the IGF‐1 signaling pathway by regulating the bioavailability of IGF‐1 (Guan et al, 2014; Singh‐Mallah et al, 2017). Further, we confirmed that IGF‐1 and IGFBP3 mRNA were endogenously expressed in hfNSCs (Figure ).…”

“…cGP has been reported to promote the activation of tyrosine phosphorylation of the IGF-1 receptors in rat brain (Guan et al, 2014) and inhibiting in mammary gland (Singh-Mallah et al, 2017), and protein phosphorylation regulates the activity of the p53 signaling pathway (Maclaine & Hupp, 2009). Therefore, we used a comprehensive protein phosphorylation array to investigate whether cGP affects the activation of intracellular signaling pathways via protein phosphorylation in hfNSCs (Figure 4a).…”

Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

“…It has been shown that this small peptide acts, as does GPE, by modulating the amount of free IGF-I, the biologically active fraction, by regulating the binding of IGF-I to its binding proteins, particularly to IGFBP3; therefore, it normalizes the function of IGF-I in pathological conditions [86,87]. In this sense, it has been shown that cGP increases the availability of free IGF-I when it is low (as occurs in the brain of RTT patients), but inhibits it when free IGF-I is in high values; this may explain why IGF-I can show such different effects as improving the recovery of brain lesions in rats and decreasing or inhibiting the growth of some tumors in mice [87], but also why cGP improves memory in adult rats [88].…”