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[sup-/-] mice were not viable because of an early embryonic lethal event. Although A5PP2[sup+/-) 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[sup+/-] mice. Primary thymocytes derived from ASPP2[sup+/+) mice exhibited an attenuated apoptotic response to γ-irradiation compared with ASPP2[sup+/-) thymocytes. Additionally. ASPP2[sup+/+] primary mouse embryonic fibroblasts demonstrated a defective G[sub0/G[sub1] cell cycle checkpoint after 7-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. [ABSTRACT FROM AUTHOR]