IngentaConnect Reduction in Cyclin D1Cdk4Retinoblastoma Protein Signaling by CRE...

Authors: Park Y.G.¹; Park S.¹; Lim S.O.¹; Lee M.S.¹; Ryu C.K.¹; Kim I.²; Cho-Chung Y.S.³

Source: Biochemical and Biophysical Research Communications, Volume 281, Number 5, March 2001 , pp. 1213-1219(7)

Abstract:

We have previously demonstrated that the activation of p53 signaling may contribute to tumor growth inhibition by the CRE-decoy oligonucleotide containing CRE sequence (5 prime -TGACGTCA-3 prime ) (Lee et al., Biochemistry 39, 4863–4868, 2000). However, growth inhibition by CRE-decoy treatment was also observed in tumor cells containing a mutant p53 (Park et al., J. Biol. Chem. 274, 1573–1580, 1999). To understand additional mechanisms of the decoy oligonucleotide, we investigated the effect on cyclin D1 expression and a cyclin D1/Cdk4/retinoblastoma protein (pRB) signaling pathway. Here we show that in MCF7 breast cancer cells the CRE-decoy competed with cyclin D1-CRE (5 prime -TAACGTCA-3 prime ) for binding transcription factors and reduced cyclin D1 gene expression (in reporter gene assay, Northern blotting and Western blotting) to modulate cyclin D1/Cdk4/pRB signaling and G1-S progression in a steady state and/or under estrogen stimulation. Decrease of cyclin D1 protein level by CRE-decoy treatment was also observed in p53-mutated cancer cells. Cyclin D1 expression was also diminished in MCF7 cells stably expressing dominant negative mutant CREB indicating that the nonspecific effect of oligonucleotide or its degradation products could be excluded. These data suggest that inhibition of cyclin D1 expression contributes to the growth inhibition induced by the decoy oligonucleotide in MCF7 cells through a cyclin D1/Cdk4/pRB signaling pathway. Downregulation of cyclin D1 expression also provides a mechanism of CRE-decoy-induced growth inhibition in tumor cells having p53 mutation. Copyright 2001 Academic Press.

Keywords: CRE-decoy oligonucleotide; cyclin D1; retinoblastoma protein; G1 phase arrest; tumor growth inhibition

Language: English

Document Type: Research article

Affiliations: 1: Department of Biochemistry 2: Department of Biochemistry, Department of Pathology, Korea University College of Medicine, Seoul, 136-701, Korea 3: Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland, 20892-1750

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Reduction in Cyclin D1/Cdk4/Retinoblastoma Protein Signaling by CRE-Decoy Oligonucleotide