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Loss of One Allele of ARF Rescues Mdm2 Haploinsufficiency Effects On Oncogene (2004) 23, 8931–8940 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development Christine M Eischen*,1,2, Jodi R Alt1,2 and Peng Wang1 1Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, NE 68198, USA; 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA The tumor suppressor p19ARF inhibits Mdm2, which ARF or p53is inactivated in over half of these tumors restricts the activity of p53. Complicated feedback and (Eischen et al., 1999). In addition, in lymphomas that control mechanisms regulate ARF, Mdm2, and p53 emerge in ARF þ /À or p53 þ /ÀEm-myc transgenics, the interactions. Here we report that ARF haploinsufficiency second allele of ARF or p53 is deleted in 77 or 100% of completely rescued the p53-dependent effects of Mdm2 these tumors, respectively (Eischen et al., 1999; Schmitt haploinsufficiency on B-cell development, survival, and et al., 1999). Therefore, ARF and p53guard against transformation. In contrast to Mdm2 þ /À B cells, Mdm2 þ /À oncogene-initiated tumorigenesis by activating apoptosis B cells deficient in ARF were similar to wild-type B cells in and consequently, are frequently targeted for inactiva- their rates of growth and apoptosis and activation of p53. tion in lymphomas that overexpress oncogenes. Consequently, the profoundly reduced numbers of B cells Mdm2 is a key intermediary in the ARF–p53tumor in Mdm2 þ /ÀEl-myc transgenic mice were restored to suppressor pathway. Mdm2 functions as an E3ubiqui- normal levels in ARF þ /ÀMdm2 þ /ÀEl-myc transgenics. tin ligase, and inactivates p53by ubiquitylating and Additionally, ARF þ /ÀMdm2 þ /ÀEl-myc transgenics devel- targeting it for degradation by the proteasome (Honda oped lymphomas at rates analogous to those observed for et al., 1997; Freedman and Levine, 1998; Roth et al., wild-type El-myc transgenics, demonstrating that loss of 1998). Mdm2 can also bind to p53and block its one allele of ARF rescued the protracted lymphoma transactivation functions (Momand et al., 1992). ARF is latency in Mdm2 þ /ÀEl-myc transgenics. Importantly, in a nucleolar protein and regulates p53by binding to ARF þ /ÀMdm2 þ /ÀEl-myc transgenic lymphomas, p53 was Mdm2 and blocking Mdm2’s ability to ubiquitylate p53 inactivated at the frequency observed in lymphomas of and to inhibit p53transcription functions (Kamijo et al., wild-type El-myc transgenics. Collectively, these results 1998; Pomerantz et al., 1998; Stott et al., 1998; Zhang support a model whereby the stoichiometry of Mdm2 and et al., 1998; Honda and Yasuda, 1999). Whereas ARF ARF controls apoptosis and tumor development, which or p53is commonly inactivated in cancers, Mdm2 should have significant implications in the treatment of is frequently overexpressed in murine and human malignancies that have inactivated ARF. malignancies, including lymphomas (Watanabe et al., Oncogene (2004) 23, 8931–8940. doi:10.1038/sj.onc.1208052 1996; Momand et al., 1998; Eischen et al., 1999). Thus, Published online 27 September 2004 ARF, Mdm2, and p53function together to suppress tumor development. Keywords: Mdm2; ARF; lymphoma; apoptosis; Myc; In vitro and in vivo experiments have shown that p53 Mdm2 is necessary to regulate p53activity during development and under stressful conditions, such as oncogene overexpression and following DNA damage. Firstly, early embryonic lethality of Mdm2-null embryos is rescued by loss of p53 (Jones et al., 1995; Montes de Introduction Oca Luna et al., 1995). Secondly, deleting p53 blocks Mdm2 haploinsufficient B cells from undergoing spon- The tumor suppressors p19ARF and p53are essential in taneous and Myc-induced apoptosis (Alt et al., 2003). blocking lymphoma development initiated by oncogenes. Thirdly, mice engineered to express low levels of Mdm2 ARF and p53mediate Myc-induced apoptosis in B cells, (hypomorphic) are more sensitive to apoptosis and and consequently loss of ARF or p53 accelerates Myc- death induced by gamma radiation, which is rescued by induced B-cell lymphomagenesis (Eischen et al., 1999; loss of p53 (Mendrysa et al., 2003). Finally, lymphomas Schmitt et al., 1999). Furthermore, in the lymphomas that arise in Mdm2 þ /ÀEm-myc transgenic mice preferen- that arise in Em-myc transgenic mice, which overexpress tially harbor mutations that inactivate p53 (Alt et al., Myc in the B-cell compartment (Adams et al., 1985), 2003). Therefore, a certain threshold of Mdm2 is required to harness p53activity under stressful condi- *Correspondence: CM Eischen; E-mail: [email protected] tions, and failure to do so results in apoptosis. Received 7 April 2004; revised 23June 2004; accepted 24 July 2004; Although at face value the p53tumor suppressor 10.1038/sj.onc.1208052; published online 27 September 2004 pathway appears linear, complicated feedback control Stoichiometry of ARF and Mdm2 regulates lymphomagenesis CM Eischen et al 8932 mechanisms are also operational in the pathway (Wu et al., 1993; Stott et al., 1998). For example, Mdm2 is a direct transcription target upregulated by p53(Barak et al., 1993; Juven et al., 1993; Perry et al., 1993; Wu et al., 1993), whereas ARF expression is elevated in cells lacking p53 or in cells harboring p53 mutations, and this appears to be Mdm2-independent (Kamijo et al., 1998; Zindy et al., 1998). However, Mdm2 expression can also influence ARF function in certain situations. For example, ARF overexpression fails to induce a cell cycle arrest in p53-null cells (Kamijo et al., 1997), yet is capable of doing so in cells lacking both p53 and Mdm2 (Weber et al., 2000). Furthermore, in fibroblasts and B cells, the induction of p53by oncogenes requires ARF (Robertson and Jones, 1998; Stott et al., 1998; Zindy et al., 1998; Eischen et al., 1999), yet nucleolar sequestration of Mdm2 by ARF is not necessarily required for p53activation (Korgaonkar et al., 2002). Collectively, these findings underscore the complexity of the ARF/Mdm2/p53network and, in particular, the consequences of ARF : Mdm2 interactions on cell survival and transformation are not resolved. Here we report that loss of only one allele of ARF fully compensates for the effects of Mdm2 haplo- insufficiency in B-cell development, survival, and transformation in Em-myc transgenic mice. The results support the model whereby the stoichiometry of the ARF–Mdm2 complex is a critical arbiter of cell survival and transformation. Figure 1 Loss of ARF confers resistance to apoptosis to Mdm2 heterozygous pre-B cells. Prior to any detectable disease, bone marrow from two ARFÀ/À mice (triangles), two ARFÀ/ÀMdm2 þ /À mice (circles), two wild-type mice (squares), and two Mdm2 þ /À mice Results (crosses) was placed into IL-7-containing medium on day 0. Cells were counted at the indicated intervals, and net population doublings of the pre-B cells was calculated. Trypan blue dye þ /À ARF loss rescues the spontaneous apoptosis of Mdm2 exclusion was used to determine viability and propidium iodide pre-B cells (PI) staining followed by flow cytometry verified cell death was apoptosis Bone marrow-derived primary Mdm2 þ /À pre-B cells undergo spontaneous apoptosis in tissue culture and therefore do not grow (Alt et al., 2003), whereas pre-B rescued by loss of ARF,asARFÀ/ÀMdm2 þ /À bone cells lacking ARF are resistant to spontaneous apoptosis marrow cultures consistently had low apoptotic indices and can proliferate indefinitely (Eischen et al., 1999; (>86% viable at day 18) similar to those of wild-type Randle et al., 2001). p53mediates the spontaneous cultures (>89% viable at day 18). Therefore, ARF loss apoptosis of Mdm2 þ /À pre-B cells (Alt et al., 2003), yet fully compensates for the apoptosis sensitivity conferred the influence ARF had on this process was unclear. We by Mdm2 haploinsufficiency in pre-B cells. Furthermore, therefore evaluated whether loss of ARF would influence as the rates of growth of wild-type and ARFÀ/ÀMdm2 þ /À the survival and growth of Mdm2 þ /À pre-B cells in vitro. pre-B cells were similar, these results also suggest that Bone marrow from ARFÀ/À, Mdm2 þ /À, ARFÀ/ÀMdm2 þ /À, Mdm2 haploinsufficiency restores normal proliferative and wild-type littermate mice was placed into IL-7- rates even in cells lacking ARF. containing medium, which selects for pre-B cells that emerge within 14 days (Eischen et al., 1999). As Loss of one allele of ARF inhibits the increased p53 previously reported, ARF-null pre-B cells grew more activity in Mdm2 þ /À lymphocytes rapidly than wild-type pre-B cells (Figure 1; Eischen et al., 1999). In contrast to Mdm2 þ /À pre-B cells, ARFÀ/À Previously, we established that p53mediated the Mdm2 þ /À pre-B cells emerged from bone marrow and spontaneous apoptosis of Mdm2 haploinsufficient B proliferated as well as wild-type pre-B cells (Figure 1). To cells (Alt et al., 2003). In addition, thymocytes from determine whether the differences in the rates of mice with an Mdm2 hypomorphic allele showed an proliferation were attributable to differences in apopto- increase in p53transcriptional activity (Mendrysa et al., sis, we measured cell viability and DNA fragmentation in 2003). To determine whether a deficiency in ARF rescues the bone marrow cultures. As anticipated, the high rates apoptosis of Mdm2 þ /À B cells by inhibiting p53, we of spontaneous apoptosis of Mdm2 þ /À bone marrow cells evaluated p53induction and activity following gamma (o29% viable at day 18; Alt et al., 2003) were fully irradiation of mice with both alleles or only one allele of Oncogene Stoichiometry of ARF and Mdm2 regulates lymphomagenesis CM Eischen et al 8933 Mdm2 and/or ARF. As expected, the levels of p53and the p53transcriptional target p21 in unirradiated splenocytes from wild-type and Mdm2 þ /À mice were below the level of detection (Figure 2a).
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