The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10–17 with a neoR gene. ASPP2−/− mice were not viable because of an early embryonic lethal event. Although ASPP2+/− mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, γ-irradiated 6-week-old ASPP2+/− mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2+/+ mice. Primary thymocytes derived from ASPP2+/− mice exhibited an attenuated apoptotic response to γ-irradiation compared with ASPP2+/+ thymocytes. Additionally, ASPP2+/− primary mouse embryonic fibroblasts demonstrated a defective G0/G1 cell cycle checkpoint after γ-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy
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