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Studies Highlight Role of bcl-2 Gene in Programmed Cell Death

Studies Highlight Role of bcl-2 Gene in Programmed Cell Death

SAN DIEGO--The bcl-2 gene, present in follicular-type B cell lymph-oma, serves as a critical checkpoint in the apoptosis pathway, and may be involved in the development of ultraviolet-induced skin cancers, in combination with the tumor-suppressor gene p53, according to two reports presented at the American Association for Cancer Research (AACR) annual meeting.

The bcl-2 apoptosis-suppressor gene is complemented by another gene, known as bax, which is involved in stimulating apoptosis, Stanley J. Korsmeyer, MD, said at the meeting in the 36th Annual Clowes Memorial Award lecture. When bax predominates, cells execute a programmed death command, but when bcl-2 is excessive, the program is interrupted and cells survive.

In their studies of bcl-2-deficient mice, Dr. Korsmeyer and his colleagues at the Howard Hughes Medical Institute at Washington University School of Medicine, St. Louis, found that the mice embryos developed normally. However, when these bcl-2-deficient mice reached adulthood, the bax gene predominated, leading to massive death of lymphocytes and the disappearance of lymphoid organs.

In contrast, in bax-deficient mice, bcl-2 predominated. These mice displayed cellular hyperplasia and aberrations in cell death during the development of the testes.

"Further study of the bcl-2 family holds the promise of improving our understanding of the pathway of programmed cell death and the aberrations in this process that result in malignancy," Dr. Korsmeyer said.

UV Radiation-Induced Apoptosis

In other research, investigators from the Department of Dermatology at Mount Sinai School of Medicine, New York, hypothesized that ultraviolet A (UVA) radiation and ultraviolet B (UVB) radiation could induce apoptosis by stimulating p53 or by downregulating the expression of bcl-2.

Using a cell line that expresses both p53 and bcl-2, the New York City investigators found that UVB radiation significantly induced the expression of p53 in a dose-dependent and time-dependent manner. Exposure to an equally cytotoxic dose of UVA radiation, however, produced no effects on p53 expression.

In contrast, UVA radiation substantially down-regulated the expression of bcl-2, whereas exposure to the same level of UVB radiation produced no change in bcl-2 expression.

Different Pathways Triggered

The researchers concluded that UVA and UVB radiation cause cell damage and induce apoptosis by triggering different signal transduction pathways, and that the balance between the expression of p53 and bcl-2 plays an important role in regulating ultraviolet radiation-induced apoptosis.

Said investigator Huachen Wei, MD, PhD: "Because mutations in p53 and overexpression of bcl-2 can result in human cancers, our findings suggest that ultraviolet radiation may provide a new approach for drug development."

 
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