The antiangiogenic factor, 16-kDa human prolactin, induces endothelial cell cycle arrest by acting at both the G0-G1 and the G2-M phases.
The 16-kDa N-terminal fragment of human prolactin (16K hPRL) is a potent antiangiogenic factor that has been shown to prevent tumor growth in a xenograph mouse model. In this paper we first demonstrate that 16K hPRL inhibits serum-induced DNA synthesis in adult bovine aortic endothelial cells. This inhibition is associated with cell cycle arrest at both the G(0)-G(1) and the G(2)-M phase. Western blot analysis revealed that 16K hPRL strongly decreases levels of cyclin D1 and cyclin B1, but not cyclin E. The effect on cyclin D1 is at least partially transcriptional, because treatment with 16K hPRL both reduces the cyclin D1 mRNA level and down-regulates cyclin D1 promoter activity. This regulation may be due to inhibition of the MAPK pathway, but it is independent of the glycogen synthase kinase-3beta pathway. Lastly, 16K hPRL induces the expression of negative cell cycle regulators, the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1). In summary, 16K hPRL inhibits serum-induced proliferation of endothelial cells through combined effects on positive and negative regulators of cell cycle progression.
Tabruyn
Sébastien P
SP
Laboratoire de Biologie Moléculaire et de Génie Génétique, Université de Liège, Allée du 6 Aout B6A, B-4000 Liège, Belgium.
Nguyen
Ngoc-Quynh-Nhu
NQ
Cornet
Anne M
AM
Martial
Joseph A
JA
Struman
Ingrid
I
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004261:DNA Replication / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D007399:Interphase / Q000187:drug effects* / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D011388:Prolactin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; C534699:CCNB1 protein, human; C493956:CDKN1A protein, human; C534700:Ccnb1 protein, mouse; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010446:Peptide Fragments; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C503760:prolactin 16-kDa fragment, human; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011388:Prolactin; D020929:Mitogen-Activated Protein Kinase Kinases