title: A novel mechanism for p53 to regulate its target gene ECK in signaling apoptosis.
abstract: Transcription factor p53 regulates its target genes through binding to DNA consensus sequence and activating the promoters of its downstream genes. The conventional p53 consensus binding sequence was defined as two copies of the 10-bp motif 5'-PuPuPuC(A/T)(T/A)GPyPyPy-3' with a spacer of 0 to 13 bp, which exists in the regulatory regions of some p53 target genes. However, there is no such p53 consensus sequence in the promoters of a number of p53-responsive genes, suggesting that there might be other mechanisms whereby p53 transactivates the promoters of its target genes. We report here that p53 uses a novel binding mechanism to regulate the transcription of epithelial cell kinase (ECK), a receptor protein-tyrosine kinase implicated in signal transduction. We show that p53 binds to a 10-bp perfect palindromic decanucleotide (GTGACGTCAC) in the ECK promoter, activates the ECK promoter, and increases the transcription of ECK. This palindrome is required for p53-mediated transactivation of the ECK promoter. ECK is highly responsive to oxidative damage that leads to cell death. Ectopic expression of ECK causes spontaneous apoptosis in breast cancer cells. We found that ectopic expression of a mutant ECK fails to induce apoptosis in cancer cells. Our findings show that p53 is a transcriptional regulator of ECK in mediating apoptosis. The discovery of the novel p53-binding motif in the promoter may lead to the identification of a new class of p53 target genes.
authors.affiliation: Department of Radiation Oncology College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Y Jenny
authors.initials: YJ
authors.lastname: Jin
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
authors.forename: Changhong
authors.initials: C
authors.lastname: Qiao
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.forename: Paul W
authors.initials: PW
authors.lastname: Brandt-Rauf
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yin
mesh_terms: D020816:Amino Acid Motifs; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; D036104:Receptor, EphA2