Figure 3. Accelerated Eμ-myc driven lymphomagenesis in Mdm2^S394A mice.

(A) Kaplan-Meier survival curves of Eμ-Myc (n = 16) and Eμ-Myc;Mdm2^S394A (n = 11) mice. Median survival times were as follows: Eμ-Myc (125.5 days) and Eμ-Myc;Mdm2^S394A (71 days). Curves were compared by Log-rank test: P < 0.0001.

(B) Representative B cell lymphomas in lymph nodes of Eμ-Myc (98 days) and Eμ-Myc;Mdm2^S394A (80 days) mice were stained by haematoxylin and eosin (top) and with an antibody specific for B220 (bottom). Scale bars represent 100 μm.

(C) The levels of Mdm2, p53 and Arf were analyzed by western blotting in a panel of Eμ-Myc;Mdm2^S394A tumors. RT-PCR confirmed that full-length Arf message was absent in 3 of 10 tumors (2^nd from bottom). p53 cDNA was sequenced for each tumor, revealing no mutations (bottom). LN, lymph node; Spl, spleen.

(D) Schematic outlining the proposed methods of p53 activation by Myc. Tumors in mice in which Mdm2 is WT select for loss of Arf or p53, or Mdm2 overexpression (Eischen et al., 1999). We propose that Mdm2^S394A mice obviate the need for p53 loss or Mdm2 overexpression by mitigating the effects of the DDR arm of Myc signaling to p53.