BID regulation by p53 contributes to chemosensitivity.
The role of the p53 protein (encoded by TP53) in tumour suppression relies partly on the ability of p53 to regulate the transcription of genes that are important in cell-cycle arrest and in apoptosis. But the apoptotic pathway mediated by p53 is not fully understood. Here we show that BID, a member of the pro-apoptotic Bcl-2 family of proteins, is regulated by p53. BID mRNA is increased in a p53-dependent manner in vitro and in vivo, with strong expression in the splenic red pulp and colonic epithelium of gamma-irradiated mice. Both the human and the mouse BID genomic loci contain p53-binding DNA response elements that bind p53 and mediate p53-dependent transactivation of a reporter gene. In addition, BID-null mouse embryonic fibroblasts are more resistant than are wild-type fibroblasts to the DNA damaging agent adriamycin and the nucleotide analogue 5-fluorouracil, both of which stabilize endogenous p53. Our results indicate that BID is a p53-responsive 'chemosensitivity gene' that may enhance the cell death response to chemotherapy.
Sax
Joanna K
JK
Laboratory of Molecular Oncology and Cell Cycle Regulation, Howard Hughes Medical Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Fei
Peiwen
P
Murphy
Maureen E
ME
Bernhard
Eric
E
Korsmeyer
Stanley J
SJ
El-Deiry
Wafik S
WS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein; D015152:Blotting, Northern; D015153:Blotting, Western; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D002469:Cell Separation; D002843:Chromatin / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D004396:Coloring Agents / Q000494:pharmacology; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D005720:Gamma Rays; D005786:Gene Expression Regulation; D006801:Humans; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011487:Protein Conformation; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013696:Temperature; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D017304:Annexin A5; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494815:Bid protein, mouse; D002352:Carrier Proteins; D002843:Chromatin; D004396:Coloring Agents; D018076:DNA, Complementary; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D008156:Luciferases; D005472:Fluorouracil