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The ability to engage enterocyte apoptosis does not predict long-term crypt survival in p53 and Msh2 deficient mice
1Cardiff School of Biosciences, University of Cardiff, CF10 3US, UK.
Abstract:
Apoptosis and long term enterocyte survival were examined in vivo after exposure to three cytotoxic agents (Cisplatin, Nitrogen Mustard and N-methyl-N-nitrosourea (NMNU/MNU)) within mice either singly or doubly mutant for p53 and Msh2. P53 deficiency caused abrogation of the immediate apoptotic response to each agent, but only led to increased survival after cisplatin treatment. Msh2 deficiency reduced the apoptotic response to each agent, but only led to increased crypt survival after NMNU treatment. Following cisplatin treatment, the response of (Msh2(-/-), p53(-/-)) mice paralleled that of the p53(-/-) mice. A delayed wave of apoptosis was observed in both p53(-/-) and (Msh2(-/-), p53(-/-)) mice demonstrating this phenomenon to be independent of functional Mismatch repair (MMR). We conclude that loss of either p53 or Msh2 dependent apoptosis does not predict long-term crypt survival in vivo, however genetic status clearly can modulate survival for some agents such as cisplatin.
Insights
Investigating p53 and Msh2 gene roles in mouse intestinal cells revealed that while p53 deficiency blocked immediate apoptosis, it only improved survival after cisplatin. Msh2 deficiency impacted apoptosis and crypt survival differently depending on the cytotoxic agent.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The tumor suppressor protein p53 and the DNA mismatch repair protein Msh2 play critical roles in cellular responses to DNA damage.
- Understanding their interplay is crucial for predicting outcomes of genotoxic cancer therapies.
Purpose of the Study:
- To investigate the roles of p53 and Msh2 in apoptosis and enterocyte survival following exposure to cytotoxic agents.
- To determine if genetic status influences long-term crypt survival in vivo.
Main Methods:
- In vivo study using mice singly or doubly mutant for p53 and Msh2.
- Exposure to cytotoxic agents: Cisplatin, Nitrogen Mustard, and N-methyl-N-nitrosourea (NMNU).
- Assessment of apoptosis and long-term enterocyte (crypt) survival.
Main Results:
- p53 deficiency abrogated immediate apoptosis but only increased survival after cisplatin.
- Msh2 deficiency reduced apoptosis and increased crypt survival after NMNU.
- A delayed apoptosis wave, independent of Mismatch Repair (MMR), was observed in p53-deficient mice.
- Combined Msh2 and p53 deficiency mirrored p53 deficiency responses.
Conclusions:
- Loss of p53 or Msh2-dependent apoptosis does not predict long-term crypt survival.
- Genetic status significantly modulates survival in response to specific cytotoxic agents like cisplatin.