Downregulation of the p53 tumor suppressor gene and upregulation of the bcl-2 gene in retinoic acid receptor alpha-deficient transgenic mice

We recently demonstrated lymphoma development in transgenic mice deficient in retinoic acid receptor a (RAR alpha). High incidence of lymphoma develop ment in this transgenic mouse model system was similar to lymphoma developm ent in p53 knockout mice. In an effort to understand the molecular basis of lymphomagenesis in RAR alpha-deficient transgenic mice, we compared the le vels of RAR alpha to the levels of p53 mRNA, and Bcl-2, and Bax proteins in lymphoid and non-lymphoid tissues and in lymphomas derived from the RAR al pha-deficient transgenic mice. The p53 mRNA levels were depleted in various tissues including spleen (similar to 96%), thymus (similar to 29%) and bon e marrow (similar to 62%) of RAR alpha-deficient transgenic mice when compa red with the normal littermates, and the reduction in p53 mRNA expression i n the various tissues examined was proportional to the reduction in RAR alp ha expression. Bcl-2 to Bax ratios were highly increased in the Lymphoid co mpartments (spleen >bone marrow >thymus) because of selective overexpressio n of Bcl-2 protein. In summary, RAR alpha downmodulation in this transgenic mouse model system was accompanied by p53 downmodulation and deregulation of Bcl-2 to Bax ratios in the lymphoid compartments.