Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds.
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, gamma-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 gamma-irradiation compared with ASPP2(+/+) thymocytes. Additionally, ASPP2(+/-) primary mouse embryonic fibroblasts demonstrated a defective G(0)/G(1) cell cycle checkpoint after gamma-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.
Kampa
Kerstin M
KM
Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.
Acoba
Jared D
JD
Chen
Dexi
D
Gay
Joel
J
Lee
Hunjoo
H
Beemer
Kelly
K
Padiernos
Emerson
E
Boonmark
Nataya
N
Zhu
Zhiyi
Z
Fan
Alice C
AC
Bailey
Alexis S
AS
Fleming
William H
WH
Corless
Christopher
C
Felsher
Dean W
DW
Naumovski
Louie
L
Lopez
Charles D
CD
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D002453:Cell Cycle / Q000528:radiation effects; D005720:Gamma Rays; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D016399:Lymphoma, T-Cell / Q000209:etiology / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009369:Neoplasms / Q000209:etiology / Q000235:genetics; D013950:Thymus Gland; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; C511437:Trp53bp2 protein, mouse; D025521:Tumor Suppressor Proteins