The ability to engage enterocyte apoptosis does not predict long-term crypt survival in p53 and Msh2 deficient mice.
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.
Cardiff School of Biosciences, University of Cardiff, CF10 3US, UK.
Owen J
OJ
Sansom
Alan R
AR
Clarke
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival; D002945:Cisplatin / Q000009:adverse effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D004268:DNA-Binding Proteins; D020895:Enterocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D008466:Mechlorethamine / Q000009:adverse effects; D008770:Methylnitrosourea / Q000009:adverse effects; D051379:Mice; D008817:Mice, Mutant Strains; D051718:MutS Homolog 2 Protein; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D008466:Mechlorethamine; D008770:Methylnitrosourea; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D002945:Cisplatin