WAF1, a potential mediator of p53 tumor suppression.
The ability of p53 to activate transcription from specific sequences suggests that genes induced by p53 may mediate its biological role as a tumor suppressor. Using a subtractive hybridization approach, we identified a gene, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line. The WAF1 gene was localized to chromosome 6p21.2, and its sequence, structure, and activation by p53 was conserved in rodents. Introduction of WAF1 cDNA suppressed the growth of human brain, lung, and colon tumor cells in culture. Using a yeast enhancer trap, a p53-binding site was identified 2.4 kb upstream of WAF1 coding sequences. The WAF1 promoter, including this p53-binding site, conferred p53-dependent inducibility upon a heterologous reporter gene. These studies define a gene whose expression is directly induced by p53 and that could be an important mediator of p53-dependent tumor growth suppression.
el-Deiry
W S
WS
Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Tokino
T
T
Velculescu
V E
VE
Levy
D B
DB
Parsons
R
R
Trent
J M
JM
Lin
D
D
Mercer
W E
WE
Kinzler
K W
KW
Vogelstein
B
B
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D002896:Chromosomes, Human, Pair 6; D003001:Cloning, Molecular; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D017931:DNA Primers; D005786:Gene Expression Regulation; D005796:Genes; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D009693:Nucleic Acid Hybridization; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D016335:Zinc Fingers
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53