DNA repair is activated in early stages of p53-induced apoptosis.
p53 is a complex molecule involved in apoptosis, cell cycle arrest, and DNA repair. Since apoptosis may play an important role in deletion of neoplastic cells, an understanding of the mechanism of p53-induced apoptosis may be critical for possible future therapeutic interventions. Recent evidence suggests that p53-induced apoptosis may involve members of the nucleotide excision repair (NER) family, linking these two cellular events. Our work using a temperature-sensitive p53 construct further analyzes p53-induced apoptosis in cultured murine mammary epithelial cells and also suggests that DNA repair plays a role in that process. Although p21 is induced in our system, apoptosis occurs without a detectable preceding G1 cell cycle arrest and independent of cellular alterations brought on by the temperature shift. In addition, clonogenic assays suggest that early stages of p53-induced apoptosis may be reversible upon removal of the apoptosis stimulus. As a possible explanation for this reversibility, our results show that general DNA repair activity increases early in p53-induced apoptosis. We also show that caspase-3 is activated at a timepoint when colony formation begins to drop, suggesting a possible mechanism for the point of no return in p53-induced apoptosis.
Geske
F J
FJ
Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Nelson
A C
AC
Lieberman
R
R
Strange
R
R
Sun
T
T
Gerschenson
L E
LE
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D053938:DNA Fragmentation; D004260:DNA Repair; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D016158:Genes, p53; D020287:In Situ Nick-End Labeling; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D008940:Mitotic Index; D011994:Recombinant Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases