Inactivation of p53 function in cultured human mammary epithelial cells turns the telomere-length dependent senescence barrier from agonescence into crisis
Inactivation of p53 function in cultured human mammary epithelial cells turns the telomere-length dependent senescence barrier from agonescence into crisis
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DOI：
10.4161/cc.6.15.4519
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发表时间：
2007-08-01
期刊：
影响因子：
4.3
通讯作者：
Stampfer, Martha R.
中科院分区：
文献类型：
--
作者：
Garbe, James C.;Holst, Charles R.;Stampfer, Martha R.
培养的人乳腺上皮细胞（HMEC）遇到两个不同的无限期生长障碍。第一个障碍，最初称为选择，可以通过细胞周期蛋白依赖性激酶抑制剂p16（INK 4A）的表达丧失来克服。产生的p16（-），p53（+）选择后HMEC遇到第二个障碍，称为衰老，与严重缩短的端粒和广泛的染色体畸变有关。尽管在衰老时存在一些细胞死亡，但大多数细胞群体仍保持长期活力.我们现在表明，在选择后HMEC中p53功能的废除使细胞周期检查点失活，并将大多数存活的衰老屏障改变为具有大量细胞死亡的危机样屏障。相反，p53的失活不影响HMEC克服第一屏障的能力。这些数据表明，衰老和危机代表了端粒长度依赖性增殖屏障的两种不同形式。总之，我们的数据表明，HMEC衰老障碍的修改模型。我们建议，第一个障碍是Rb介导的，很大程度上或完全独立的端粒长度。这个屏障现在被称为停滞期，指的是与压力相关的衰老.第二个障碍（衰老或危象）是由于持续的端粒侵蚀导致端粒严重缩短和端粒功能障碍。
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 p16(INK4A). 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.