Tissue-specific induction of p53 targets in vivo.
The in vivo response to radiotherapy is not well understood but appears to involve the p53 tumor suppressor protein. We investigated the expression of apoptosis-inducing p53 target genes during gamma-irradiation-induced cell death in p53(+/+) or p53(-/-) mouse tissues using in situ hybridization. Our results reveal striking tissue specificity with distinct regulation of target p53-induced genes in different cells and tissue compartments, as well as variations in dependence on p53 for basal expression. p53-dependent induction of Puma occurred in the splenic white pulp, whereas Noxa and Bid were induced in the red pulp. These patterns correlated with activation of caspase-3 in both compartments. All apoptotic targets of p53 studied here (DR5, Bid, Puma, Noxa) were induced in the jejunum and ileum, which appeared to be the tissues most sensitive to irradiation. We also observed unexpected differences in p53 target gene activation between the transverse and descending colon. Finally, in the liver where irradiation did not lead to caspase-3 activation, we primarily observed p21(WAF1) induction as the major p53-dependent target gene response. Our findings indicate that the selectivity of p53 in transactivation following DNA damage in vivo results in unique tissue and cell type specificity, which may correlate with growth arrest or variable sensitivity to gamma-irradiation.
Fei
Peiwen
P
Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Department of Medicine, University of Pennsylvania School of Medicine and Abramson Cancer Center, Philadelphia, Pennsylvania 19104, USA.
Bernhard
Eric J
EJ
El-Deiry
Wafik S
WS
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003106:Colon / Q000378:metabolism / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000502:physiology* / Q000528:radiation effects; D008099:Liver / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000378:metabolism / Q000528:radiation effects; D013950:Thymus Gland / Q000378:metabolism / Q000528:radiation effects; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505640:Tnfrsf10b protein, mouse; D016159:Tumor Suppressor Protein p53; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases