Laboratory of Functional Anatomy, Department of Life Sciences, Faculty of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki, Kanagawa 214-8571, Japan.
J Mol Endocrinol. 2014 Apr 28;52(3):279-87. doi: 10.1530/JME-13-0189. Print 2014 Jun.
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.
血管抑制素是一类作用于内皮细胞的肽，可抑制血管生成并促进凋亡介导的血管退化。血管抑制素包括催乳素 (PRL)、GH 和胎盘催乳素的 N 端片段。其中一种血管抑制素，即 16 kDa 的 PRL N 端片段，是由溶酶体代表性蛋白酶组织蛋白酶 D (Cath D) 产生的。由于乳腺 (MG) 的正常生长和退化受到血管扩张和退化的深刻影响，并且 PRL 刺激 MG 的生长和分化，因此我们假设哺乳期产生的完整 PRL 有助于 MG 血管生成和增加血流量，而在退化过程中，PRL 的 N 端片段会对乳腺上皮细胞 (MECs) 产生促凋亡作用。因此，我们研究了 N 端 PRL 片段的产生及其对 MG 的直接影响。鼠 PRL (mPRL) 被 Cath D 在氨基酸 148 和 149 之间进行蛋白水解切割。N 端 PRL 片段和 Cath D 的表达在 MG 退化过程中增加。此外，将 MG 片段和 MCF7 与重组 16 kDa mPRL 孵育，显示 MECs 发生凋亡。MG 溶酶体部分中的 Cath D 将 MECs 中的异位 mPRL 切割为 16 kDa PRL。来自垂体的大部分 PRL 在培养基中被切割为 16 kDa PRL。因此，N 端 PRL 片段在退化期增加，对 MECs 具有促凋亡作用，主要由 MG 细胞外空间中分泌的 Cath D 产生。
