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Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular

Kerstin M Kampa1, Jared D Acoba, Dexi Chen

  • 1Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 3, 2009
PubMed

Insights

ASPP2 (apoptosis-associated speck-like protein containing a CARD domain) is a tumor suppressor. Loss of one ASPP2 gene copy in mice led to spontaneous tumors and impaired DNA damage response, indicating haploinsufficiency.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ASPP2 (apoptosis-associated speck-like protein containing a CARD domain) is a tumor suppressor frequently downregulated in human cancers.
  • Evidence suggests ASPP2 inhibits tumor growth, but its precise mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of ASPP2 in tumor suppression using a genetically modified mouse model.
  • To elucidate the mechanisms underlying ASPP2's tumor-suppressive functions.

Main Methods:

  • Generated ASPP2 knockout mice by replacing exons 10-17 with a neoR gene.
  • Analyzed tumor incidence, apoptosis, and cell cycle checkpoints in ASPP2 heterozygous (+/-) and wild-type (+/+) mice.
  • Exposed mice to gamma-irradiation to assess DNA damage response.

Main Results:

  • ASPP2(-/-) mice exhibited embryonic lethality.
  • ASPP2(+/-) mice showed increased spontaneous tumor incidence and susceptibility to radiation-induced lymphomas.
  • ASPP2 haploinsufficiency resulted in attenuated apoptosis and defective G(0)/G(1) cell cycle arrest in response to DNA damage.

Conclusions:

  • ASPP2 acts as a haploinsufficient tumor suppressor.
  • Disruption of ASPP2 pathways contributes to tumorigenesis and impacts response to cancer therapy.

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