Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.
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.
Lee
S B
SB
Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.
Kim
S H
SH
Bell
D W
DW
Wahrer
D C
DC
Schiripo
T A
TA
Jorczak
M M
MM
Sgroi
D C
DC
Garber
J E
JE
Li
F P
FP
Nichols
K E
KE
Varley
J M
JM
Godwin
A K
AK
Shannon
K M
KM
Harlow
E
E
Haber
D A
DA
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
D018076:DNA, Complementary; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases