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Lee SB , Kim SH , Bell DW , Wahrer DCR , Schiripo TA , Jorczak MM , Sgroi DC , Garber JE , Li FP , Nichols KE , Varley JM , Godwin AK , Shannon KM , Harlow E , Haber DA
Destabilization of CHK2 by a missense mutation associated with Li- Fraumeni syndrome
Cancer Research. 2001 Nov 15;61(22) :8062-8067
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Li Fraumeni Syndrome (LFS) is a multicancer phenotype, most commonly associated with germ-line mutations in TP53. In a kindred with LFS without an inherited TP53 mutation, we have previously reported a truncating mutation (1100delC) in CHK2, encoding a kinase that phosphorylates p53 on Ser(20). Here, we describe a CHK2 missense mutation (R145W) in another LFS family. This mutation destabilizes the encoded protein, reducing its half-life from > 120 min to 30 min. This effect is abrogated by treatment of cells with a proteosome inhibitor, suggesting that CHK2(R145W) is targeted through this degradation pathway. Both 1100delC and R145W germ-line mutations in CHK2 are associated with loss of the wild-type allele in the corresponding tumor specimens, and neither tumor harbors a somatic TP53 mutation. Our observations support the functional significance of CHK2 mutations in rare cases of LFS and suggest that such mutations may substitute for inactivation of TP53.
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