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| Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bar in H2O2 response of normal human fibroblasts |
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| Author(s): Chen QM, Liu JP, Merrett JB |
| Source: BIOCHEMICAL JOURNAL Volume: 347 Pages: 543-551 Part: Part 2 Published: APR 15 2000 |
| Times Cited: 109 References: 54 |
| Abstract: Early-passage human diploid fibroblasts (HDFs) undergo senescence-like growth arrest in response to sublethal concentrations of H2O2 [Chen and Ames (1994) Proc. Natl. Acad. Sci. U.S.A. 95, 4130-4134]. We determine here whether H2O2 can cause apoptosis in HDFs and the molecular changes that differ between apoptosis and senescence-like growth arrest. When exponentially growing early-passage IMR-90 cells were treated for 2 h with 50-200 mu M (or 0.25-1 pmol/cell) H2O2, a fraction of cells detached at 16-32 h after the treatment. The cells remaining attached were growth-arrested and developed features of senescence in 1 week. The detached cells showed caspase-3 activation and typical morphological changes associated with apoptosis. Caspase-3 activation was H2O2 dose-dependent and preceded nuclear condensation or plasma membrane leakage. Apoptotic cells were mainly distributed in the S-phase of the cell cycle, while growth-arrested cells exhibited predominantly G1- and G2/M-phase distributions. H2O2 pretreatment induced G1 arrest and prohibited induction of apoptosis by a subsequent H2O2 challenge. The p53 protein showed an average 6.1-fold elevation in apoptotic cells and a 3.5-fold elevation in growth-arrested cells. Reduction of p53 levels with human papillomavirus E6 protein prohibited the activation of caspase-3 and decreased the proportion of apoptotic cells. Growth-arrested cells had elevated p21, while p21 was absent in apoptotic cells. Bcl-2 was elevated in both growth-arrested and apoptotic cells. Finally, although the overall level of bar did not change in growth-arrested or apoptotic cells, the solubility of bar protein increased in apoptotic cells. Our data suggest that in contrast with growth-arrested cells, apoptotic cells show an S-phase cell cycle distribution, a higher degree of p53 elevation, an absence of p21 protein and increased solubility of bar protein. |
| Document Type: Article |
| Language: English |
| Reprint Address: Chen, QM (reprint author), Univ Arizona, Dept Pharmacol, Skaggs Pharmaceut Sci Bldg,Room 130,1703 E Mabel, Tucson, AZ 85721 USA |
Addresses:
1. Univ Arizona, Dept Pharmacol, Tucson, AZ 85721 USA |
| Publisher: PORTLAND PRESS, 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND |
| Subject Category: Biochemistry & Molecular Biology |
| IDS Number: 309WT |
| ISSN: 0264-6021 |
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