title: 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.
authors.affiliation: Liggins Institute, University of Auckland, Auckland, New Zealand.|AgResearch Ltd., Ruakura Research Centre, Hamilton, New Zealand.|Gravida, National Centre for Growth and Development, Liggins Institute, University of Auckland, Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Gagandeep
authors.initials: G
authors.lastname: Singh-Mallah
authors.affiliation: AgResearch Ltd., Ruakura Research Centre, Hamilton, New Zealand.|Gravida, National Centre for Growth and Development, Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: McMahon
authors.affiliation: Gravida, National Centre for Growth and Development, Liggins Institute, University of Auckland, Auckland, New Zealand.|Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Brain Research New Zealand, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Faculty of Medical and Health Sciences, Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
authors.affiliation: AgResearch Ltd., Ruakura Research Centre, Hamilton, New Zealand.|Gravida, National Centre for Growth and Development, Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Kuljeet
authors.initials: K
authors.lastname: Singh
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019394:Ki-67 Antigen; D010456:Peptides, Cyclic; C000628795:cyclic glycine-proline; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: IGF-1; apoptosis; cyclic-glycine-proline; involution