title: Vasoinhibins, N-terminal mouse prolactin fragments, participate in mammary gland involution.
abstract: Vasoinhibins are a family of peptides that act on endothelial cells to suppress angiogenesis and promote apoptosis-mediated vascular regression. Vasoinhibins include the N-terminal fragments from prolactin (PRL), GH, and placental lactogen. One of the vasoinhibins, the N-terminal PRL fragment of 16 kDa, is generated by the lysosomal representative protease cathepsin D (Cath D). Because the normal growth and involution of the mammary gland (MG) are profoundly affected by the expansion and regression of blood vessels and also because PRL stimulates the growth and differentiation of MG, we proposed that intact PRL produced during lactation contributes to MG angiogenesis and increased blood flow, whereas during involution, the N-terminal PRL fragment would have proapoptotic effects on mammary epithelial cells (MECs). Therefore, we investigated the production of the N-terminal PRL fragment and its direct effect on the MG. Mouse PRL (mPRL) was proteolytically cleaved by Cath D between amino acids 148 and 149. N-terminal PRL fragment and Cath D expression increased during MG involution. Furthermore, incubation of MG fragments and MCF7 with recombinant 16 kDa mPRL revealed a proapoptotic effect in MECs. Ectopic mPRL in MECs was cleaved to 16 kDa PRL by Cath D in the MG lysosomal fraction. The majority of PRL derived from pituitary gland was cleaved to 16 kDa PRL in culture medium. Therefore, N-terminal PRL fragment increases during the involution period, has a proapoptotic effect on MECs, and is mainly generated by secreted Cath D in the extracellular space of MG.
authors.affiliation: Laboratory of Functional Anatomy, Department of Life Sciences, Faculty of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Ishida
authors.forename: Midori
authors.initials: M
authors.lastname: Maehara
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yu
authors.initials: Y
authors.lastname: Yanagisawa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Takata
authors.forename: Ryojun
authors.initials: R
authors.lastname: Nakajima
authors.forename: Mika
authors.initials: M
authors.lastname: Suzuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Harigaya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002402:Cathepsin D / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D006801:Humans; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000098:blood supply / Q000254:growth & development / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D011388:Prolactin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011981:Receptors, Prolactin / Q000096:biosynthesis / Q000235:genetics; D020539:Sequence Analysis, Protein
chemical_list: D018797:Cell Cycle Proteins; D012333:RNA, Messenger; D011981:Receptors, Prolactin; C510089:Vash1 protein, mouse; D011388:Prolactin; D002402:Cathepsin D; C533923:Ctsd protein, mouse
keywords: ectopic expression; mammary gland; mouse; prolactin