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Originally published In Press as doi:10.1074/jbc.M212919200 on June 11, 2003

J. Biol. Chem., Vol. 278, Issue 34, 32465-32470, August 22, 2003
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The MEK/ERK Pathway Acts Upstream of NF{kappa}B1 (p50) Homodimer Activity and Bcl-2 Expression in a Murine B-Cell Lymphoma Cell Line

MEK INHIBITION RESTORES RADIATION-INDUCED APOPTOSIS*

John F. Kurland, David W. Voehringer and Raymond E. Meyn {ddagger}

From the Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

In a previously published report (Kurland, J. F., Kodym, R., Story, M. D., Spurgers, K. B., McDonnell, T. J., and Meyn, R. E. (2001) J. Biol. Chem. 276, 45380–45386), we described the NF{kappa}B status for two murine B-cell lymphoma cell lines, LY-as (apoptosis-sensitive) and LY-ar (apoptosis-refractory) and provided evidence that NF{kappa}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 tumor necrosis factor-{alpha}, an I{kappa}B kinase activator, did not alter the suppressive effect of PD 98059 on p50 homodimer activity, suggesting an I{kappa}B kinase-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.

Received for publication, December 18, 2002 , and in revised form, June 7, 2003.

* This work was supported in part by National Institutes of Health Grant CA69003. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

{ddagger} To whom correspondence should be addressed: 1515 Holcombe Blvd., Box 66, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. Tel.: 713-792-3424; Fax: 713-794-5369; E-mail: rmeyn{at}mdanderson.org.


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