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ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth
Virginie Vives1, Jian Su, Shan Zhong
1Ludwig Institute for Cancer Research, University College London, London W1W 7BS, United Kingdom.
Abstract:
ASPP2 stimulates the apoptotic function of the p53 family in vivo. We show here that ASPP2-/- pups died before weaning. This postnatal lethality was significantly enhanced in p53+/- background and both deletions are synthetic lethal. ASPP2+/- mice developed spontaneous tumors. The tumor onset was accelerated by gamma-irradiation or in p53+/- background. Tumors derived from ASPP2+/- mice retained wild-type ASPP2 allele even though some of them lost p53. These provide the first genetic evidence that ASPP2 is a haploinsufficient tumor suppressor that shares overlapping function(s) with p53 in mouse development and tumor suppression.
Insights
The ankyrin repeat and SOCS box-containing protein 2 (ASPP2) is essential for development and tumor suppression. Loss of ASPP2 causes early death and spontaneous tumors, highlighting its role alongside p53.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The ankyrin repeat and SOCS box-containing protein 2 (ASPP2) is known to interact with the p53 family of proteins.
- ASPP2 is implicated in regulating apoptosis and cellular growth.
Purpose of the Study:
- To investigate the in vivo function of ASPP2 in development and tumor suppression.
- To determine the genetic interaction between ASPP2 and p53.
Main Methods:
- Generation and analysis of ASPP2 knockout (ASPP2-/-) and heterozygous (ASPP2+/-) mice.
- Assessment of developmental phenotypes, including postnatal lethality.
- Induction of tumors via gamma-irradiation and analysis of tumor development in different genetic backgrounds (p53+/-).
- Genotyping of tumors to assess ASPP2 and p53 allele status.
Main Results:
- ASPP2-/- mice exhibited postnatal lethality, which was exacerbated in a p53+/- background, indicating synthetic lethality.
- ASPP2+/- mice developed spontaneous tumors, with accelerated onset following gamma-irradiation or in a p53+/- background.
- Tumors from ASPP2+/- mice often retained the wild-type ASPP2 allele but sometimes lost p53, suggesting ASPP2 acts as a haploinsufficient tumor suppressor.
Conclusions:
- ASPP2 is a haploinsufficient tumor suppressor with functions overlapping those of p53 in mouse development and cancer prevention.
- The genetic interaction between ASPP2 and p53 is critical for preventing developmental lethality and spontaneous tumorigenesis.
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