Bethesda, MD - Scientists have discovered a DNA sequence that causes the destabilization, and hence decay, of the protooncogene bcl-2 (B-cell lymphoma/leukemia-2). Because the overexpression of bcl-2 is associated with cancer, this discovery may lead to new therapeutic strategies for treating the disease.
The research appears as the "Paper of the Week" in the October 8 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.
Bcl-2 is a gene that, when mutated or inappropriately expressed, can cause a cell to become cancerous. Normally, bcl-2 produces a protein that inhibits cell death or apoptosis. This protein keeps death-promoting factors from producing holes in the mitochondria which can result in calcium and destructive proteins leaking out into the cell. However, the overexpression of bcl-2 in damaged cells can lead to the continued division of the mutated cells and eventually cancer.
The expression of the bcl-2 gene is regulated both transcriptionally and posttranscriptionally. One way bcl-2 levels are controlled is through an adenine and uracil-rich sequence of nucleotides in the 3' untranslated region of the bcl-2 mRNA. This sequence, called the AU-rich element, or ARE, recruits a number of proteins that destabilize the bcl-2 mRNA, resulting in its degradation.
A report that a region of RNA upstream of the ARE also affects mRNA stability motivated Dr. Jeong-Hwa Lee and his colleagues at the Catholic University of Korea to make a series of bcl-2 mRNA constructs with deletions around the ARE.
From these constructs, the investigators identified a region of 30 nucleotides outside the ARE that destabilizes bcl-2 mRNA both in the absence and in the presence of the ARE. Because the region is composed mostly of cytosine and adenine repeats, they named it the CA-repeated Region (CAR).
The discovery of a new region on the bcl-2 gene that controls its expression may be big news for cancer therapy. Several drugs that reduce the amount of bcl-2 present in the cell are already used in chemotherapy to induce apoptosis and overcome drug resistance in cancer cells.
Jung-Hee Lee, Mi-Hee Jeon, Yun-Jee Seo, Yong-Joon Lee, Jeong Heon Ko, Yoshihide Tsujimoto, and Jeong-Hwa Lee
CA Repeats in the 3'-Untranslated Region of bcl-2 mRNA Mediate Constitutive Decay of bcl-2 mRNA
J. Biol. Chem. 2004 279: 42758-42764.
The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be accessed directly from the home page of the Journal of Biological Chemistry online at http://www.jbc.org.
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Message posted by: Frank S. Zollmann