Alternative and aberrant splicing of MDM2 mRNA in human cancer Frank Bartel, Helge Taubert, Linda C Harris  Cancer Cell  Volume 2, Issue 1, Pages 9-15 (July 2002) DOI: 10.1016/S1535-6108(02)00091-0

Figure 1 MDM2—structure and function A: Model depicting the well characterized interactions between MDM2 and p53. p53 activates transcription of MDM2. MDM2 protein in turn binds to p53 and acts as an E3 ubiquitin ligase that targets p53 for degradation by the proteasome, thereby inhibiting its own transcription. B: Structure of full-length human MDM2 protein and the cDNA that encodes it. The domains of the human MDM2 protein and the binding sites of various proteins are indicated. ID1, ID2: growth inhibitory domains 1 and 2 (Brown et al., 1998). NES: nuclear export sequence. NLS: nuclear localization sequence. NoLS: cryptic nucleolar localization signal. Cancer Cell 2002 2, 9-15DOI: (10.1016/S1535-6108(02)00091-0)

Figure 2 Summary of all known MDM2 mRNA splice variants and the domains that they encode. MDM2-FL refers to full-length MDM2 mRNA. At least some of the splice variants, labeled with “∗”, can be translated into protein in vitro. The sequence that is omitted in most splice forms is highlighted in gray. The number in parentheses indicates the reference: (1) Sigalas et al., 1996; (2) Bartel et al., 2001; (3) Bartel et al., 2002; (4) Lukas et al., 2001; (5) Tamborini et al., 2001; (6) Kraus et al., 1999; (7) Schlott et al., 2001; (8) Hori et al., 2000; and (9) F.B., unpublished data. Cancer Cell 2002 2, 9-15DOI: (10.1016/S1535-6108(02)00091-0)

Figure 3 Mechanism of aberrant splicing at repetitive sequences. MDM2-FL refers to full-length MDM2 mRNA. The different shaded areas represent the domains of MDM2 as shown in Figure 1 (see text for details). Cancer Cell 2002 2, 9-15DOI: (10.1016/S1535-6108(02)00091-0)

Figure 4 A model suggesting how MDM2 splice variants with an intact C terminus, for example MDM2-B, might exhibit contrasting functions. In “normal” cells, MDM2 binds to and inhibits the function of wild-type p53, promoting cell growth. When MDM2 splice variants are expressed, they bind to full-length MDM2 protein, releasing p53, resulting in growth inhibition. In transformed cells when p53 may be mutated or not expressed, MDM2 can still promote cell growth. Under these circumstances, there may be no consequence of splice variant expression, because splice variant binding to full-length MDM2 would not release any wild-type p53. Under certain conditions, full-length MDM2 expression in a transformed cell results in apoptosis or growth inhibition. If splice variants are expressed in these cells, they may bind and inhibit the growth-inhibitory function of full-length protein, resulting in an increased rate of proliferation. Cancer Cell 2002 2, 9-15DOI: (10.1016/S1535-6108(02)00091-0)