Characterization of turner-associated Chk2 mutations

Citation
Xl. Wu et al., Characterization of turner-associated Chk2 mutations, J BIOL CHEM, 276(4), 2001, pp. 2971-2974
Citations number
15
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
4
Year of publication
2001
Pages
2971 - 2974
Database
ISI
SICI code
0021-9258(20010126)276:4<2971:COTCM>2.0.ZU;2-U
Abstract
The integrity of the DNA damage response pathway is essential for preventio n of neoplastic transformation. Several proteins involved in this pathway i ncluding p53, BRCA1, and ATM are frequently mutated in human cancer. Checkp oint kinase 2 (Chk2) is a DNA damage-activated protein kinase that lies dow nstream of ATM in this pathway. Recently, heterozygous germline mutations i n Chk2 have been identified in a subset of patients with Li-Fraumeni syndro me, a highly penetrant familial cancer phenotype, suggesting that Chk2 is a tumor suppressor gene. In this study, we have reported the biochemical cha racterization of the four tumor-associated Chk2 mutants. Two of the reporte d Chk2 mutations identified in Li-Fraumeni syndrome result in loss of Chk2 kinase activity, Whereas one mutation within the Chk2 forkhead homology-ass ociated (FHA) domain, R145W, retains some basal kinase activity, this mutan t cannot be phosphorylated at an ATM-dependent phosphorylation site (Thr-68 ) and cannot be activated following gamma radiation. Wild-type Chk2 exists mainly in a protein complex of M-r similar to 200,000 whereas the R145W mut ant forms a larger, presumably inactive complex in the cell. The other FHA domain mutant, I157T, behaves as wild-type Chk2 in all the assays used here . Because the FHA domain is involved in protein-protein interactions, this mutation may affect associations of Chk2 with other proteins. Additionally, we have shown that Chk2 can also be inactivated by down-regulation of its expression in cancer cells. Thus, Chk2 may be inactivated by multiple mecha nisms in the cell.