Loss of the p21(Cip1/Waf1) cyclin kinase inhibitor results in propagation of horizontally transferred DNA.
We have shown previously that phagocytosis of cells dying by apoptosis results in transfer of whole or fragments of chromosomes into the nucleus of the recipient cell. Although DNA transfer was detected in normal cells, stable propagation of the transferred DNA was only observed in cells deficient in p53. Here we show that mouse embryonic fibroblast cells lacking the p21 (Cip1/Waf1) cyclin-kinase inhibitor are able to propagate DNA engulfed by phagocytosis of apoptotic bodies. Feeding mouse embryonic fibroblast p21(-/-) cells with apoptotic bodies derived from a rat fibrosarcoma resulted in focus formation in vitro and tumor formation in vivo. In contrast, cells lacking the p19 alternative reading frame gene did not show any evidence of transformation. These data indicate that p53, via the activation of p21, blocks normal cells from replicating transferred DNA from engulfed apoptotic bodies. This may be one protection level against the propagation of potentially pathological DNA.
Bergsmedh
Anna
A
Cancer Center Karolinska Hospital, Karolinska Institutet, S-171 76 Stockholm, Sweden.
Szeles
Anna
A
Spetz
Anna-Lena
AL
Holmgren
Lars
L
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002934:Cinnamates; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000235:genetics; D005354:Fibrosarcoma / Q000235:genetics / Q000473:pathology; D018014:Gene Transfer Techniques; D016259:Genes, myc; D006801:Humans; D006921:Hygromycin B / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D010587:Phagocytosis; D051381:Rats; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; C417743:Cdkn2a protein, mouse; D002934:Cinnamates; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004273:DNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D006921:Hygromycin B; C026273:hygromycin A