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A novel mechanism for p53 to regulate its target gene ECK in signaling apoptosis.

Authors
Jin-YJ; Wang-J; Qiao-C; Hei-TK; Brandt-Rauf-PW; Yin-Y
Source
Mol Cancer Res 2006 Oct; 4(10):769-778
NIOSHTIC No.
20038418
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.
Keywords
Cancer; Gene-mutation; Genes; DNA-damage; Tumors; Protein-biochemistry; Proteins; Cell-function; Oxidative-processes; Breast-cancer; Molecular-biology; Amino-acids; Humans; Genetics; Author Keywords: p53; palindrome; ECK; EphA2; oxidative stress; apoptosis
Contact
Yuxin Yin, Department of Radiation Oncology College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA
CODEN
MCROC5
Publication Date
20061001
Document Type
Journal Article
Email Address
yy151@columbia.edu
Funding Type
Grant
Fiscal Year
2007
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-007590
Issue of Publication
10
ISSN
1541-7786
Priority Area
Research Tools and Approaches: Cancer Research Methods
Source Name
Molecular Cancer Research
State
NY
Performing Organization
Columbia University Health Sciences
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