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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.

Pubmed ID: 19251665

Authors

  • Kampa KM
  • Acoba JD
  • Chen D
  • Gay J
  • Lee H
  • Beemer K
  • Padiernos E
  • Boonmark N
  • Zhu Z
  • Fan AC
  • Bailey AS
  • Fleming WH
  • Corless C
  • Felsher DW
  • Naumovski L
  • Lopez CD

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 17, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: 5-P30-CA69533
  • Agency: NCI NIH HHS, Id: CA076316
  • Agency: NCI NIH HHS, Id: CA104997
  • Agency: NCI NIH HHS, Id: CA85773
  • Agency: NCI NIH HHS, Id: CA89305
  • Agency: NHLBI NIH HHS, Id: HL069133
  • Agency: NHLBI NIH HHS, Id: HL077818
  • Agency: NCI NIH HHS, Id: P01 CA034233

Mesh Terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • Cell Cycle
  • Gamma Rays
  • Genetic Predisposition to Disease
  • Heterozygote
  • Lymphoma, T-Cell
  • Mice
  • Mice, Mutant Strains
  • Neoplasms
  • Thymus Gland
  • Tumor Suppressor Proteins