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Submitted on May 17, 2004
Accepted on June 4, 2004
INSERM Unit 584, Hormone Targets, Faculté de Médecine Necker, 75730, Paris Cedex 15, France; Laboratory of Molecular Biology and Genetic Engineering, University of Liège, B-4000, Sart Tilman, Belgium; Laboratoire de Chimie Structurale Organique et Biologique; Batiment F, Université Pierre et Marie Curie, Paris, France, and Neurobiology Institute, National Autonomous University of Mexico
* To whom correspondence should be addressed. E-mail: goffin{at}necker.fr.
16K prolactin (PRL) is the name given to the 16 kDa N-terminal fragment obtained by proteolysis of rat PRL by tissue extracts or cell lysates, in which cathepsin D was identified as the candidate protease. Based on its anti-angiogenic activity, 16K PRL is potentially a physiological inhibitor of tumor growth. Full length human (h)PRL was reported to be resistant to cathepsin D, suggesting that anti-angiogenic 16K PRL may be physiologically irrelevant in humans. In this study, we show that hPRL can be cleaved by Cathepsin D or mammary cell extracts under the same conditions as described earlier for rat PRL, although with lower efficiency. In contrast to the rat hormone, hPRL proteolysis generates three 16K-like fragments, which were identified by N-terminal sequencing and mass spectrometry as corresponding to amino acids 1-132 (15 kDa), 1-147 (16.5 kDa) and 1-150 (17 kDa). Biochemical and mutagenenis studies showed that the species-specific digestion pattern is due to subtle differences in primary and tertiary structures of rat and human hormones. The anti-angiogenic activity of N-terminal hPRL fragments was assessed by the inhibition of growth factor-induced thymidine uptake and MAP kinase activation in bovine umbilical endothelial cells. Finally, an N-terminal hPRL fragment co-migrating with the proteolytic 17 kDa fragment was identified in human pituitary adenomas, suggesting that the physiological relevance of anti-angiogenic N-terminal hPRL fragments needs to be re-evaluated in humans.
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