p16(INK4a)-mediated suppression of telomerase in normal and malignant human breast cells

Bazarov, A. V., van Sluis, M., Hines, W. C., Bassett, E., Beliveau, A., Campeau, E., Mukhopadhyay, R., Lee, W. J., Melodyev, S., Zaslavsky, Y., Lee, L., Rodier, F., Chicas, A., Lowe, S. W., Benhattar, J., Ren, B., Campisi, J., Yaswen, P. (October 2010) p16(INK4a)-mediated suppression of telomerase in normal and malignant human breast cells. Aging Cell, 9 (5). pp. 736-746. ISSN 1474-9718

URL: http://www.ncbi.nlm.nih.gov/pubmed/20569236
DOI: 10.1111/j.1474-9726.2010.00599.x

Abstract

P>The cyclin-dependent kinase inhibitor p16INK4a (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.

Item Type: Paper
Uncontrolled Keywords: heterochromatin histone methylation hTERT INK4a senescence EMBRYONIC STEM-CELLS REVERSE-TRANSCRIPTASE EXPRESSION RETINOBLASTOMA TUMOR-SUPPRESSOR MAMMARY EPITHELIAL-CELLS HISTONE H3 LYSINE-27 CELLULAR SENESCENCE HTERT GENE HETEROCHROMATIN FORMATION DEVELOPMENTAL REGULATORS DIFFERENTIAL ROLES
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders > cancer > cancer types > breast cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
therapies > stem cells
CSHL Authors:
Communities: CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL labs > Lowe lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: CSHL Librarian
Date: October 2010
Date Deposited: 26 Sep 2011 13:46
Last Modified: 13 Oct 2015 19:28
PMCID: PMC2941554
Related URLs:
URI: http://repository.cshl.edu/id/eprint/15351

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