p16(INK4a) -mediated suppression of telomerase in normal and malignant human breast cells.
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.
Bazarov
Alexey V
AV
Department of Laboratory Medicine, University of California, San Francisco, USA.
Van Sluis
Marjolein
M
Hines
William C
WC
Bassett
Ekaterina
E
Beliveau
Alain
A
Campeau
Eric
E
Mukhopadhyay
Rituparna
R
Lee
Won Jae
WJ
Melodyev
Sonya
S
Zaslavsky
Yuri
Y
Lee
Leonard
L
Rodier
Francis
F
Chicas
Agustin
A
Lowe
Scott W
SW
Benhattar
Jean
J
Ren
Bing
B
Campisi
Judith
J
Yaswen
Paul
P
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
D019941:Cyclin-Dependent Kinase Inhibitor p16; D006657:Histones; D012333:RNA, Messenger; C509186:TERT protein, human; D019098:Telomerase