title: Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.
abstract: 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.
authors.affiliation: Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Lee
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: D W
authors.initials: DW
authors.lastname: Bell
authors.forename: D C
authors.initials: DC
authors.lastname: Wahrer
authors.forename: T A
authors.initials: TA
authors.lastname: Schiripo
authors.forename: M M
authors.initials: MM
authors.lastname: Jorczak
authors.forename: D C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: J E
authors.initials: JE
authors.lastname: Garber
authors.forename: F P
authors.initials: FP
authors.lastname: Li
authors.forename: K E
authors.initials: KE
authors.lastname: Nichols
authors.forename: J M
authors.initials: JM
authors.lastname: Varley
authors.forename: A K
authors.initials: AK
authors.lastname: Godwin
authors.forename: K M
authors.initials: KM
authors.lastname: Shannon
authors.forename: E
authors.initials: E
authors.lastname: Harlow
authors.forename: D A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000328:Adult; D001483:Base Sequence; D064447:Checkpoint Kinase 2; D003110:Colonic Neoplasms / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000201:enzymology / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
chemical_list: D018076:DNA, Complementary; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases