title: Transforming growth factor-beta, estrogen, and progesterone converge on the regulation of p27Kip1 in the normal and malignant endometrium.
abstract: Hormones and growth factors regulate endometrial cell growth. Disrupted transforming growth factor-beta (TGF-beta) signaling in primary endometrial carcinoma (ECA) cells leads to loss of TGF-beta-mediated growth inhibition, which we show herein results in lack of up-regulation of the cyclin-dependent kinase inhibitor p27(Kip1) (p27) to arrest cells in G(1) phase of the cell cycle. Conversely, in normal primary endometrial epithelial cells (EECs), TGF-beta induces a dose-dependent increase in p27 protein, with a total 3.6-fold maximal increase at 100 pmol/L TGF-beta, which was 2-fold higher in the nuclear fraction; mRNA levels were unaffected. In addition, ECA tissue lysates show a high rate of ubiquitin-mediated degradation of p27 compared with normal secretory-phase endometrial tissue (SE) such that 4% and 89% of recombinant p27 added to the lysates remains after 3 and 20 h, respectively. These results are reflected in vivo as ECA tissue lacks p27 compared with high expression of p27 in SE (P < or = 0.001). Furthermore, we show that estrogen treatment of EECs causes mitogen-activated protein kinase-driven proteasomal degradation of p27 whereas progesterone induces a marked increase in p27 in both normal EECs and ECA cells. Therefore, these data suggest that TGF-beta induces accumulation of p27 for normal growth regulation of EECs. However, in ECA, in addition to enhanced proteasomal degradation of p27, TGF-beta cannot induce p27 levels due to dysregulated TGF-beta signaling, thereby causing 17beta-estradiol-driven p27 degradation to proceed unchecked for cell cycle progression. Thus, p27 may be a central target for growth regulation of normal endometrium and in the pathogenesis of ECA.
authors.affiliation: Departments of Pathology and Medicine, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Lecanda
authors.forename: Trilok V
authors.initials: TV
authors.lastname: Parekh
authors.forename: Patricia
authors.initials: P
authors.lastname: Gama
authors.forename: Ke
authors.initials: K
authors.lastname: Lin
authors.forename: Vladimir
authors.initials: V
authors.lastname: Liarski
authors.forename: Seth
authors.initials: S
authors.lastname: Uretsky
authors.forename: Khush
authors.initials: K
authors.lastname: Mittal
authors.forename: Leslie I
authors.initials: LI
authors.lastname: Gold
mesh_terms: D000328:Adult; D048708:Cell Growth Processes / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003593:Cytoplasm / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004727:Endothelium / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000096:biosynthesis
chemical_list: C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014452:Ubiquitins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011374:Progesterone; D004958:Estradiol; D020928:Mitogen-Activated Protein Kinases