DNA sequence controls expression of gene involved in cancer

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.