The authors injected an adenovirus expressing Cre recombinase (Ad-Cre) into the muscles of the extremities of mice to induce the expression of conditional mutations in KrasG12D and Trp53. More than 90% of the mice developed STS when both mutant genes were expressed (confirmed by PCR). However, if the mice were infected with Ad-GFP (green fluorescent protein), or carried one wild-type Trp53 allele, no sarcomas developed. Moreover, of 53 mice with mutant Trp53 but wild-type Kras, only one developed STS. Therefore, cooperation between Kras and mutated Trp53 was necessary for efficient sarcomagenesis.
So, how do expression of KrasG12D and inactivation of Trp53 cooperate in this mouse model? Aberrant oncogene expression can induce the expression of ARF, which sequesters MDM2, a negative regulator of p53, thereby allowing p53 to function as a tumour suppressor. In line with this, David Kirsch et al. found that the proteins encoded by the
Cdkn2a
locus — INK4a and ARF — are upregulated in the STS found in their mouse model, but not in normal skeletal muscle from the same mouse. These results indicate that the Cdkn2a locus can respond to oncogenic KRAS in mesenchymal tissues to suppress sarcomagenesis through p53. Consistent with this hypothesis, the authors showed that deletion of Cdkn2a, but not key components of the intrinsic pathway of apoptosis downstream of p53 — Bak1 or Bax — could substitute for the mutation of p53. This suggests that sarcoma suppression by p53 in this model occurs by cell-cycle arrest or senescence and not by apoptosis.
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