title: p16(INK4a) -mediated suppression of telomerase in normal and malignant human breast cells.
abstract: The cyclin-dependent kinase inhibitor p16(INK4a) (CDKN2A) is an important tumor suppressor gene frequently inactivated in human tumors. p16 suppresses the development of cancer by triggering an irreversible arrest of cell proliferation termed cellular senescence. Here, we describe another anti-oncogenic function of p16 in addition to its ability to halt cell cycle progression. We show that transient expression of p16 stably represses the hTERT gene, encoding the catalytic subunit of telomerase, in both normal and malignant breast epithelial cells. Short-term p16 expression increases the amount of histone H3 trimethylated on lysine 27 (H3K27) bound to the hTERT promoter, resulting in transcriptional silencing, likely mediated by polycomb complexes. Our results indicate that transient p16 exposure may prevent malignant progression in dividing cells by irreversible repression of genes, such as hTERT, whose activity is necessary for extensive self-renewal.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, USA.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Bazarov
authors.forename: Marjolein
authors.initials: M
authors.lastname: Van Sluis
authors.forename: William C
authors.initials: WC
authors.lastname: Hines
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Bassett
authors.forename: Alain
authors.initials: A
authors.lastname: Beliveau
authors.forename: Eric
authors.initials: E
authors.lastname: Campeau
authors.forename: Rituparna
authors.initials: R
authors.lastname: Mukhopadhyay
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Lee
authors.forename: Sonya
authors.initials: S
authors.lastname: Melodyev
authors.forename: Yuri
authors.initials: Y
authors.lastname: Zaslavsky
authors.forename: Leonard
authors.initials: L
authors.lastname: Lee
authors.forename: Francis
authors.initials: F
authors.lastname: Rodier
authors.forename: Agustin
authors.initials: A
authors.lastname: Chicas
authors.forename: Scott W
authors.initials: SW
authors.lastname: Lowe
authors.forename: Jean
authors.initials: J
authors.lastname: Benhattar
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.forename: Paul
authors.initials: P
authors.lastname: Yaswen
mesh_terms: D001940:Breast / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase