p53変異は蛋白凝集も生じさせる : 癌もまた蛋白misfolding疾患?



Nature Chemical Biologyにて、 p53の有る変異が、蛋白の折りたたみを生じさせ、凝集を開始する、そういうあたらしい、変異p53の働きが明らかになった。

Gain of function of mutant p53 by coaggregation with multiple tumor suppressors
Jie Xu et al
Nature Chemical Biology

構造的不安定化p53変異は、この影響により野生種p53やp63やp73のパラログの凝集を生じ、heat-shock responseを誘導する。 変異p53の凝集により、変異後暴露されたDNA結合ドメイン親水性核内に凝集
Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation.

Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.

by internalmedicine | 2011-03-30 11:40 | がん  

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