Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.
AuthorsLee, S B
Kim, S H
Bell, D W
Wahrer, D C
Schiripo, T A
Jorczak, M M
Sgroi, D C
Garber, J E
Li, F P
Nichols, K E
Godwin, A K
Shannon, K M
Haber, D A
AffiliationMassachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.
MetadataShow full item record
AbstractLi 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.
CitationDestabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. 2001, 61 (22):8062-7 Cancer Res.
- Characterization of tumor-associated Chk2 mutations.
- Authors: Wu X, Webster SR, Chen J
- Issue date: 2001 Jan 26
- p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition.
- Authors: Vahteristo P, Tamminen A, Karvinen P, Eerola H, Eklund C, Aaltonen LA, Blomqvist C, Aittomäki K, Nevanlinna H
- Issue date: 2001 Aug 1
- Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype.
- Authors: Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA
- Issue date: 2003 Oct 15
- [Li-Fraumeni syndrome: update, new data and guidelines for clinical management].
- Authors: Frebourg T, Abel A, Bonaiti-Pellie C, Brugières L, Berthet P, Bressac-de Paillerets B, Chevrier A, Chompret A, Cohen-Haguenauer O, Delattre O, Feingold J, Feunteun J, Frappaz D, Fricker JP, Gesta P, Jonveaux P, Kalifa C, Lasset C, Leheup B, Limacher JM, Longy M, Nogues C, Oppenheim D, Sommelet D, Soubrier F, Stoll C, Stoppa-Lyonnet D, Tristant H
- Issue date: 2001 Jun
- Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families.
- Authors: Varley JM, McGown G, Thorncroft M, Santibanez-Koref MF, Kelsey AM, Tricker KJ, Evans DG, Birch JM
- Issue date: 1997 Aug 1