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Papers In Press, published online ahead of print June 11, 2003
Experimental Radiation Oncology, U.T. M. D. Anderson Cancer Center, Houston, TX 77030
Corresponding Author: rmeyn{at}mdanderson.org
In a previously published report, we described the NF-
J. Biol. Chem, 10.1074/jbc.M212919200
Submitted on December 18, 2002
Revised on June 7, 2003
Accepted on June 11, 2003
The MEK/ERK pathway acts upstream of NF-
B1 (p50) homodimer activity and Bcl-2 expression in a murine B-Cell lymphoma cell line: MEK inhibition restores radiation - induced apoptosis
B status for two murine B cell lymphoma cell lines, LY-as (apoptosis sensitive) and LY-ar (apoptosis refractory), and provided evidence that NF-B1 (p50) homodimers contribute to the expression of Bcl-2 in the LY-ar line. In the present study, we investigated the upstream signals leading to p50 homodimer activation and Bcl-2 expression. We found that in LY-ar cells, ERK1 and ERK2 were constitutively phosphorylated, whereas LY-as cells had no detectable ERK1 or ERK2 phosphorylation. Treatment of LY-ar cells with the MEK inhibitors PD 98059, U0126, and PD 184352 led to a loss of phosphorylated ERK1 and ERK2, a reversal of nuclear p50 homodimer DNA binding, and a decrease in Bcl-2 protein expression. Similarly, activation of the MEK/ERK pathway in LY-as cells by phorbol ester led to Bcl-2 expression that could be blocked by PD 98059. Furthermore, treatment of LY-ar cells with TNF
, an IKK activator, did not alter the suppressive effect of PD 98059 on p50 homodimer activity, suggesting an IKK-independent pathway for p50 homodimer activation. Lastly, all three MEK inhibitors sensitized LY-ar cells to radiation-induced apoptosis. We conclude that the MEK/ERK pathway acts upstream of p50 homodimer activity and Bcl-2 expression in this B-cell lymphoma cell system and suggest that the use of MEK inhibitors could be useful clinically in combination with ionizing radiation to treat lymphoid malignancies.
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