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-irra- diated 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 G 0/G 1 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 tumori- genesis and response to therapy.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - Mar 17 2009|
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