title: CRE-transcription factor decoy oligonucleotide inhibition of MCF-7 breast cancer cells: cross-talk with p53 signaling pathway.
abstract: The CRE, 5'-TGACGTCA-3', has been described as the consensus sequence for the cis-element that directs cAMP-regulated gene expression. Many transcription factors bind to this element and regulate the expression of a wide variety of cellular and viral genes. We have shown that CRE-transcription factor decoy oligonucleotide restrains the growth of cancer cells in vitro and in vivo [Park, Y. G., Nesterova, M., Agrawal, S., and Cho-Chung, Y. S. (1999) J. Biol. Chem. 274, 1573-1580]. The growth inhibition was accompanied by changes in cell morphology and apoptosis. To elucidate the molecular mechanism(s) of the growth inhibition by the CRE-decoy oligonucleotide, we investigated the p53 signaling pathway. Herein, we report that CRE-decoy oligonucleotide treatment results in an increase in the p53 protein level in MCF-7 human breast cancer cells that express wild-type p53. The p21WAF1/Cip1 protein levels were also increased in the CRE-decoy oligonucleotide treated cells accompanying a reduction in Cdk2- and cyclin E-dependent kinase activity and pRb phosphorylation. Pulse-chase experiments reveal that the p53 upregulation was due to increased stability of the protein. The decoy oligonucleotide treatment also enhanced the p53 promotor-directed transcription in vivo along with the increase in p53-CBP (CREB-binding protein) complex formation. Thus, the stabilization and activation of p53 may have contributed to the growth inhibition induced by CRE-transcription factor decoy oligonucleotide in MCF-7 breast cancer cells. This decoy oligonucleotide approach offers great promise as a tool for defining cellular regulatory processes and treating cancer and other diseases.
authors.affiliation: Cellular Biochemistry Section, Laboratory of Tumor Immunology and Biology, and Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892-1750, USA.
authors.forename: Y N
authors.initials: YN
authors.lastname: Lee
authors.forename: Y G
authors.initials: YG
authors.lastname: Park
authors.forename: Y H
authors.initials: YH
authors.lastname: Choi
authors.forename: Y S
authors.initials: YS
authors.lastname: Cho
authors.forename: Y S
authors.initials: YS
authors.lastname: Cho-Chung
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D042846:CDC2-CDC28 Kinases; D050882:CREB-Binding Protein; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000502:physiology*; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013816:Thermodynamics; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D009841:Oligonucleotides; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases