TY - JOUR
T1 - Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds
AU - Kampa, Kerstin M.
AU - Acoba, Jared D.
AU - Chen, Dexi
AU - Gay, Joel
AU - Lee, Hunjoo
AU - Beemer, Kelly
AU - Padiernos, Emerson
AU - Boonmark, Nataya
AU - Zhu, Zhiyi
AU - Fan, Alice C.
AU - Bailey, Alexis S.
AU - Fleming, William H.
AU - Corless, Christopher
AU - Felsher, Dean W.
AU - Naumovski, Louie
AU - Lopez, Charles D.
PY - 2009/3/17
Y1 - 2009/3/17
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.0809080106
DO - 10.1073/pnas.0809080106
M3 - Article
C2 - 19251665
AN - SCOPUS:63149117341
SN - 0027-8424
VL - 106
SP - 4390
EP - 4395
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -