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Inactivation of p53 Function in Cultured Human Mammary Epithelial Cells Turns the Telomere-Length Dependent Senescence Barrier from Agonescence into Crisis

James C. Garbe, Charles R. Holst, Ekaterina Bassett, Thea Tlsty and Martha R. Stampfer

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Cultured human mammary epithelial cells (HMEC) encounter two distinct barriers to indefinite growth. The first barrier, originally termed selection, can be overcome through loss of expression of the cyclin-dependent kinase inhibitor p16INK4A. The resultant p16(-), p53(+) post-selection HMEC encounter a second barrier, termed agonescence, associated with critically shortened telomeres and widespread chromosomal aberrations. Although some cell death is present at agonescence, the majority of the population retains long-term viability. We now show that abrogation of p53 function in post-selection HMEC inactivates cell cycle checkpoints and changes the mostly viable agonescence barrier into a crisis-like barrier with massive cell death. In contrast, inactivation of p53 does not affect the ability of HMEC to overcome the first barrier. These data indicate that agonescence and crisis represent two different forms of a telomere-length dependent proliferation barrier. Altogether, our data suggest a modified model of HMEC senescence barriers. We propose that the first barrier is Rb-mediated and largely or completely independent of telomere length. This barrier is now being termed stasis, for stress-associated senescence. The second barrier (agonescence or crisis) results from ongoing telomere erosion leading to critically short telomeres and telomere dysfunction.

Authors

James C. Garbe

Lawrence Berkeley National Laboratory; Berkeley CA USA

Charles R. Holst

University of California San Francisco; San Francisco, CA USA

Ekaterina Bassett

Lawrence Berkeley National Laboratory; Berkeley, CA USA

Thea Tlsty

University of California San Francisco; San Francisco, CA USA

Martha R. Stampfer

Lawrence Berkeley National Laboratory; Berkeley, CA USA

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.