NF-κB1 Can Inhibit v-Abl-Induced Lymphoid Transformation by Functioning as a Negative Regulator of Cyclin D1 Expression

Abstract

Mounting evidence implicates deregulated Rel/NF-κB signaling as a common feature of lymphoid malignancies. Despite the fact that they promote the survival and proliferation of normal lymphocytes, the underlying mechanisms by which various Rel/NF-κB proteins with different transcriptional regulatory capacities might facilitate transformation remain to be established. Here we show that the proliferation and tumorigenicity of Abelson murine leukemia virus (A-MuLV)-transformed pre-B cells are enhanced in the absence of NF-κB1 and that this coincides with elevated levels of cyclin D1. Support for a link between cyclin D1 expression and v-Abl transformation came from the finding that proliferation of transformed pre-B cells was reduced in the absence of cyclin D1, while enforced cyclin D1 expression increased the proliferation and tumorigenicity of wild-type transformants. A reduction in endogenous cyclin D1 levels that coincided with NF-κB1 transgene reversal of enhanced nfkb1^−/− pre-B-cell transformation, coupled with NF-κB1 inhibition of v-Abl-induced κB-dependent murine cyclin D1 transcription, lends support to a model in which v-Abl-induced cyclin D1 transcription in transformed pre-B cells is controlled by Rel/NF-κB dimers with different activities.

We thank D. Baltimore (Caltech, Pasadena, Calif.) for providing the nfkb1 ^−/− and rela ^−/− mice; C. Dickson for generous provision of the mouse cyclin D1 genomic clone and cyd1 ^−/− mice; S. Cory, J. Adams, A. Strasser, D. Huang, W. Heath, and A. Elephanty (WEHI, Melbourne, Australia) and G. McArthur (Peter MacCallum Cancer Institute, Melbourne, Australia) for reagents; and lab members M. Grossmann and R. Gugasyan for help and discussions. We also acknowledge J. Merryfull and G. Siciliano for expert assistance with animal husbandry and F. Battye and colleagues for assistance with cell sorting.

This work was supported by the National Health and Medical Research Council of Australia, the Anti-Cancer Council of Victoria, a Commonwealth AIDS Research Grant (no. 971274), the International Association for Cancer Research (St. Andrews, United Kingdom), and the Leukemia and Lymphoma Society of America. Y.N. was a recipient of a fellowship from the Uehara Memorial Foundation (Tokyo, Japan).