The expression of prolactin and its cathepsin D-mediated cleavage in the bovine corpus luteum vary with the estrous cycle.

In the corpus luteum (CL), blood vessels develop, stabilize, and regress. This process depends on the ratio of pro- and antiangiogenic factors, which change during the ovarian cycle. The present study focuses on the possible roles of 23,000 (23K) prolactin (PRL) in the bovine CL and its antiangiogenic NH(2)-terminal fragments after extracellular cleavage by cathepsin D (Cath D). PRL RNA and protein were demonstrated in the CL tissue, in luteal endothelial cells, and in steroidogenic cells. Cath D was detected in CL tissue, cell extracts, and corresponding cell supernatants. In the intact CL, 23K PRL levels decreased gradually, whereas Cath D levels concomitantly increased between early and late luteal stages. In vitro, PRL cleavage occurred in the presence of acidified homogenates of CL tissue, cells, and corresponding cell supernatants. Similar fragments were obtained with purified Cath D, and their appearance was inhibited by pepstatin A. The aspartic protease specific substrate MOCAc-GKPILF~FRLK(Dnp)-D-R-NH(2) was cleaved by CL cell supernatants, providing further evidence for Cath D activity. The 16,000 PRL inhibited proliferation of luteal endothelial cells accompanied by an increase in cleaved caspase-3. In conclusion, 1) the bovine CL is able to produce PRL and to process it into antiangiogenic fragments by Cath D activity and 2) PRL cleavage might mediate angioregression during luteolysis.

[1]  H. Kalbacher,et al.  A new approach for distinguishing cathepsin E and D activity in antigen‐processing organelles , 2007, The FEBS journal.

[2]  R. Hill,et al.  Hypoxia and Metastasis , 2007, Clinical Cancer Research.

[3]  Carlo Follo,et al.  Folding, activity and targeting of mutated human cathepsin D that cannot be processed into the double-chain form. , 2007, The international journal of biochemistry & cell biology.

[4]  J. Grosche,et al.  The Short Prolactin Receptor Predominates in Endothelial Cells of Micro- and Macrovascular Origin , 2006, Journal of Vascular Research.

[5]  P. Kelly,et al.  A new mechanism for prolactin processing into 16K PRL by secreted cathepsin D. , 2006, Molecular endocrinology.

[6]  J. Rivera,et al.  Matrix metalloproteases from chondrocytes generate an antiangiogenic 16 kDa prolactin , 2006, Journal of Cell Science.

[7]  K. Okuda,et al.  Bovine corpus luteum is an extrapituitary site of prolactin production , 2006, Molecular reproduction and development.

[8]  Lin Yan,et al.  Autophagy in chronically ischemic myocardium. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  P. Maini,et al.  The role of acidity in solid tumour growth and invasion. , 2005, Journal of theoretical biology.

[10]  J. Martial,et al.  The antiangiogenic factor, 16-kDa human prolactin, induces endothelial cell cycle arrest by acting at both the G0-G1 and the G2-M phases. , 2005, Molecular endocrinology.

[11]  V. Hedgpeth,et al.  Expression and localization of hypoxia inducible factor-1alpha mRNA in the porcine ovary. , 2005, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[12]  E. Skrzydlewska,et al.  Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. , 2005, World journal of gastroenterology.

[13]  A. Noël,et al.  Catalytically inactive human cathepsin D triggers fibroblast invasive growth , 2005, The Journal of cell biology.

[14]  P. Huber,et al.  Cytokeratin expression in bovine corpora lutea , 1995, Histochemistry and Cell Biology.

[15]  N. Binart,et al.  Corpus luteum development: lessons from genetic models in mice. , 2005, Current topics in developmental biology.

[16]  T. Kupiec,et al.  Effects of estrone on N-METHYL-d-aspartic acid- and staurosporine-induced changes in caspase-3-like protease activity and lactate dehydrogenase-release: time- and tissue-dependent effects in neuronal primary cultures , 2004, Neuroscience.

[17]  A. Miyamoto,et al.  Endothelin-1 within the Corpus Luteum during Spontaneous Luteolysis in the Cow: Local Interaction with Prostaglandin F2α and Angiotensin II , 2004, Journal of cardiovascular pharmacology.

[18]  J. Illera,et al.  Cellular localization and changes in expression of prolactin receptor isoforms in sheep ovary throughout the estrous cycle. , 2004, Reproduction.

[19]  R. Gillies,et al.  Why do cancers have high aerobic glycolysis? , 2004, Nature Reviews Cancer.

[20]  J. Martial,et al.  Cathepsin D processes human prolactin into multiple 16K-like N-terminal fragments: study of their antiangiogenic properties and physiological relevance. , 2004, Molecular endocrinology.

[21]  C. Isidoro,et al.  Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions , 2004, Journal of Cell Science.

[22]  D. Maiti,et al.  Plasmalemmal V-H(+)-ATPases regulate intracellular pH in human lung microvascular endothelial cells. , 2004, Biochemical and biophysical research communications.

[23]  J. Rivera,et al.  Prolactin in eyes of patients with retinopathy of prematurity: implications for vascular regression. , 2004, Investigative ophthalmology & visual science.

[24]  C. Isidoro,et al.  Preconditioning-induced cytoprotection in hepatocytes requires Ca2+-dependent exocytosis of lysosomes , 2004, Journal of Cell Science.

[25]  K. Spanel‐Borowski,et al.  Diversity of ultrastructure in different phenotypes of cultured microvessel endothelial cells isolated from bovine corpus luteum , 1991, Cell and Tissue Research.

[26]  P. Hoyer,et al.  Cellular composition and steroidogenic capacity of the ovary of Macrotus californicus (Chiroptera: Phyllostomatidae) during and after delayed embryonic development , 1990, Cell and Tissue Research.

[27]  H. Jabbour,et al.  Cyclooxygenase-2 overexpression inhibits cathepsin D-mediated cleavage of plasminogen to the potent antiangiogenic factor angiostatin. , 2003, Endocrinology.

[28]  B. Rueda,et al.  Microvascular endothelial cells of the corpus luteum , 2003, Reproductive biology and endocrinology : RB&E.

[29]  K. Öllinger,et al.  Cathepsin D mediates cytochrome c release and caspase activation in human fibroblast apoptosis induced by staurosporine , 2003, Cell Death and Differentiation.

[30]  N. Arakaki,et al.  Possible role of cell surface H+ -ATP synthase in the extracellular ATP synthesis and proliferation of human umbilical vein endothelial cells. , 2003, Molecular cancer research : MCR.

[31]  J. Martial,et al.  The antiangiogenic factor 16K human prolactin induces caspase-dependent apoptosis by a mechanism that requires activation of nuclear factor-kappaB. , 2003, Molecular endocrinology.

[32]  H. Du,et al.  Lysosomal Enzymes Are Released From Cultured Human Macrophages, Hydrolyze LDL In Vitro, and Are Present Extracellularly in Human Atherosclerotic Lesions , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[33]  L. Mazzucchelli,et al.  Cathepsin D Specifically Cleaves the Chemokines Macrophage Inflammatory Protein-1α, Macrophage Inflammatory Protein-1β, and SLC That Are Expressed in Human Breast Cancer , 2003 .

[34]  P. Kelly,et al.  Effects of deletion of the prolactin receptor on ovarian gene expression , 2003, Reproductive biology and endocrinology : RB&E.

[35]  森河 亘.  Angiostatin generation by cathepsin D secreted by human prostate carcinoma cells , 2003 .

[36]  L. Mazzucchelli,et al.  Cathepsin D specifically cleaves the chemokines macrophage inflammatory protein-1 alpha, macrophage inflammatory protein-1 beta, and SLC that are expressed in human breast cancer. , 2003, The American journal of pathology.

[37]  V. Vetvicka,et al.  Procathepsin D in breast cancer: What do we know? Effects of ribozymes and other inhibitors , 2002, Cancer Gene Therapy.

[38]  G. Berchem,et al.  Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis , 2002, Oncogene.

[39]  B. Ahlemeyer,et al.  Release of cytochrome c into the extracellular space contributes to neuronal apoptosis induced by staurosporine , 2002, Brain Research.

[40]  C. Clapp,et al.  Roles of prolactin and related members of the prolactin/growth hormone/placental lactogen family in angiogenesis. , 2002, The Journal of endocrinology.

[41]  V. Laurent-Matha,et al.  A mutated cathepsin-D devoid of its catalytic activity stimulates the growth of cancer cells , 2001, Oncogene.

[42]  Y. Uchiyama.  Autophagic cell death and its execution by lysosomal cathepsins. , 2001, Archives of histology and cytology.

[43]  Katarina Kågedal,et al.  The FASEB Journal express article 10.1096/fj.00-0708fje. Published online May 18, 2001. The lysosomal protease cathepsin D mediates apoptosis induced by oxidative stress , 2022 .

[44]  E. Vuorio,et al.  Differential expression patterns of cathepsins B, H, K, L and S in the mouse ovary. , 2001, Molecular human reproduction.

[45]  R. Hill,et al.  pH, hypoxia and metastasis. , 2001, Novartis Foundation symposium.

[46]  M. Miyazaki,et al.  Secretion of Extracellular Matrix (Fibronectin), Growth Factor (Transforming Growth Factor β) and Protease (Cathepsin D) by Hepatoma Cells , 2000, Oncology.

[47]  G. Nagy,et al.  Prolactin: structure, function, and regulation of secretion. , 2000, Physiological reviews.

[48]  J. Juengel,et al.  Mechanisms controlling the function and life span of the corpus luteum. , 2000, Physiological reviews.

[49]  A. Akamine,et al.  Characterization of new fluorogenic substrates for the rapid and sensitive assay of cathepsin E and cathepsin D. , 1999, Journal of biochemistry.

[50]  J. McCRACKEN,et al.  Luteolysis: a neuroendocrine-mediated event. , 1999, Physiological reviews.

[51]  J. Martial,et al.  Opposing actions of intact and N-terminal fragments of the human prolactin/growth hormone family members on angiogenesis: an efficient mechanism for the regulation of angiogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[52]  A. Buckley,et al.  Proteolysis of human prolactin: resistance to cathepsin D and formation of a nonangiostatic, C-terminal 16K fragment by thrombin. , 1999, Endocrinology.

[53]  Z. Dueñas,et al.  Expression of prolactin mRNA and of prolactin-like proteins in endothelial cells: evidence for autocrine effects. , 1998, The Journal of endocrinology.

[54]  P. Kelly,et al.  Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. , 1998, Endocrine reviews.

[55]  J. Kay,et al.  Cathepsin E. The best laid plans of mice and men. , 1998, Advances in experimental medicine and biology.

[56]  F. Gaytán,et al.  Role of prolactin in the regulation of macrophages and in the proliferative activity of vascular cells in newly formed and regressing rat corpora lutea. , 1997, Biology of reproduction.

[57]  M. Neeman,et al.  Regulation of angiogenesis by hypoxic stress: from solid tumours to the ovarian follicle , 1997, International journal of experimental pathology.

[58]  N. Ben-Jonathan,et al.  Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. , 1996, Endocrine reviews.

[59]  R. Meidan,et al.  Regulation of endothelin-1 expression in the bovine corpus luteum: elevation by prostaglandin F 2 alpha. , 1996, Endocrinology.

[60]  R. Maciewicz,et al.  Activation of cathepsin B, secreted by a colorectal cancer cell line requires low pH and is mediated by cathepsin D , 1996, International journal of cancer.

[61]  H. Augustin,et al.  Cyclic angiogenesis and blood vessel regression in the ovary: blood vessel regression during luteolysis involves endothelial cell detachment and vessel occlusion. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[62]  K. Yamamoto.  Cathepsin E and cathepsin D: biosynthesis, processing and subcellular location. , 1995, Advances in experimental medicine and biology.

[63]  P. Huber,et al.  Isolation of granulosal‐like cells from the bovine secretory corpus luteum and their characterization in long‐term culture , 1994 .

[64]  H. Leese,et al.  The effect of glucose metabolism on murine follicle development and steroidogenesis in vitro. , 1994, Human reproduction.

[65]  P. Huber,et al.  Isolation of granulosa-like cells from the bovine secretory corpus luteum and their characterization in long-term culture. , 1994, The Anatomical record.

[66]  D. King,et al.  Mass spectrometric analysis of the fragments produced by cleavage and reduction of rat prolactin: evidence that the cleaving enzyme is cathepsin D. , 1993, Endocrinology.

[67]  J. Scammell,et al.  Epitope mapping of monoclonal antibodies to bovine prolactin. , 1992, The American journal of physiology.

[68]  C. S. Nicoll,et al.  Processing of rat prolactin by rat tissue explants and serum in vitro. , 1992, Endocrinology.

[69]  W. Künzel,et al.  Oxygen tension in follicular fluid falls with follicle maturation. , 1992, European journal of obstetrics, gynecology, and reproductive biology.

[70]  B. Hoflack,et al.  Distribution of newly synthesized lysosomal enzymes in the endocytic pathway of normal rat kidney cells , 1991, The Journal of cell biology.

[71]  J. Griffiths.  Are cancer cells acidic? , 1991, British Journal of Cancer.

[72]  F. Rentier-Delrue,et al.  Bacterial production and purification of recombinant human prolactin , 1990, Biotechnology and applied biochemistry.

[73]  K. Spanel‐Borowski,et al.  Different phenotypes of cultured microvessel endothelial cells obtained from bovine corpus luteum. Study by light microscopy and by scanning electron microscopy (SEM). , 1990, Cell and tissue research.

[74]  S. Grinstein,et al.  A vacuolar type H(+)-ATPase regulates cytoplasmic pH in murine macrophages. , 1990, The Journal of biological chemistry.

[75]  T. Saku,et al.  Quantitation and immunohistochemical localization of cathepsins E and D in rat tissues and blood cells. , 1989, Biochimica et biophysica acta.

[76]  S. Dieleman,et al.  [The role of prolactin during the estrus cycle of cattle]. , 1988, Tijdschrift voor diergeneeskunde.

[77]  H. Rochefort,et al.  In vitro degradation of extracellular matrix with Mr 52,000 cathepsin D secreted by breast cancer cells. , 1988, Cancer research.

[78]  C. Clapp.  Analysis of the proteolytic cleavage of prolactin by the mammary gland and liver of the rat: characterization of the cleaved and 16K forms. , 1987, Endocrinology.

[79]  G. Selstam,et al.  Influence of oxygen tension and substrates on basal and luteinizing hormone stimulated progesterone production and energy metabolism by isolated corpora lutea of adult pseudopregnant rats. , 1987, Acta physiologica Scandinavica.

[80]  E. Kardalinou,et al.  Demonstration of mRNAs for oxytocin and prolactin in porcine granulosa and luteal cells , 1986, FEBS letters.

[81]  R. Gosden,et al.  Oxygen concentration gradient across the ovarian follicular epithelium: model, predictions and implications. , 1986, Human reproduction.

[82]  D. Delbeke,et al.  Comparison of patterns of prolactin release in GH4C1 cells and primary pituitary cultures , 1985, Molecular and Cellular Endocrinology.

[83]  R. Pain,et al.  Conformation and processing of cathepsin D , 1985, Bioscience reports.

[84]  E. Schallenberger,et al.  The role of prolactin in the regulation of the primate corpus luteum. , 1985, The Journal of clinical endocrinology and metabolism.

[85]  M. Compton,et al.  Proteolytic degradation and modification of rat prolactin by subcellular fractions of the rat ventral prostate gland. , 1984, Endocrinology.

[86]  K. von Figura,et al.  Biosynthesis and transport of cathepsin D in cultured human fibroblasts , 1983, The Journal of cell biology.

[87]  K. von Figura,et al.  Lysosomal enzyme precursors in human fibroblasts. Activation of cathepsin D precursor in vitro and activity of beta-hexosaminidase A precursor towards ganglioside GM2. , 1982, European journal of biochemistry.

[88]  J. Rall,et al.  Effects of three prostaglandin analogues on lysosomal enzyme activities and ultrastructural morphology of luteal cells in the chacma baboon. , 1981, South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde.

[89]  J. Downing,et al.  Luteinizing hormone receptors and testosterone synthesis in two distinct populations of Leydig cells. , 1980, Endocrinology.

[90]  J. Dingle,et al.  Lysosomal alterations in hypoxic and reoxygenated hearts. II. Immunohistochemical and biochemical changes in cathepsin D. , 1980, The American journal of pathology.

[91]  J. Ireland,et al.  Accuracy of predicting stages of bovine estrous cycle by gross appearance of the corpus luteum. , 1980, Journal of dairy science.

[92]  R. Meidan,et al.  Intracellular distribution of cathepsin D in rat corpora lutea in relation to reproductive state and the action of prostaglandin F2alpha and prolactin. , 1977, The Journal of endocrinology.

[93]  W. Chamley,et al.  Changes in small blood vessels during cyclical luteal regression in sheep. , 1977, Biology of reproduction.

[94]  J. Dingle,et al.  Altered distribution of lysosomal cathepsin D in ischemic myocardium. , 1977, The Journal of clinical investigation.

[95]  G. Thorburn,et al.  Morphology of the corpus luteum in the sheep during regression induced by prostaglandin F2ALPHA. , 1976, Biology of reproduction.

[96]  P. A. Kurup,et al.  Vitamin A and lysosomal stability in rat liver. , 1974, The Journal of nutrition.

[97]  R. Moor,et al.  Lysosomal function in the corpus luteum of the sheep. , 1968, The Journal of endocrinology.