Aberrations of the Chk2 tumour suppressor in advanced urinary bladder cancer

Jirina Bartkova, Per Guldberg, Kirsten Grønbaek, Karen Koed, Hanne Primdahl, Klaus Møller, Jiri Lukas, Torben F Ørntoft, Jiri Bartek

Abstract

Checkpoint kinase 2 (Chk2) is a tumour suppressor and signal transducer in genome integrity checkpoints that coordinate cell-cycle progression with DNA repair or cell death in response to DNA damage. Defects of Chk2 occur in subsets of diverse sporadic malignancies and predispose to several types of hereditary carcinomas. However, the status of Chk2 in tumours of the urinary bladder remains unknown. Here, we report that among 58 advanced (grade T2-T4) human bladder carcinomas, immunohistochemical analysis revealed tumour-specific reduction or lack of Chk2 protein in 6 (10.3%) cases. Genetic analysis of the latter subset showed that a Chk2-negative carcinoma #668 harboured a truncating mutation 1100delC, in one Chk2 allele and loss of the corresponding second allele. The 1100delC mutation was also found in the germ line of this patient. Sequencing of TP53 in tumour #668 identified two missense mutations. Furthermore, the vast majority of the tumours showed 'unscheduled' activatory phosphorylation on Thr68 of Chk2 in the absence of any DNA-damaging treatment. Our results indicate that the otherwise dormant DNA damage signal transducer Chk2 is aberrantly and constitutively activated in invasive urinary bladder carcinomas, and that such likely proapoptotic checkpoint signalling can be disabled by inactivation of Chk2 and/or p53 tumour suppressors in subsets of these tumours.

OriginalsprogEngelsk
TidsskriftOncogene
Vol/bind23
Udgave nummer52
Sider (fra-til)8545-51
Antal sider7
ISSN0950-9232
DOI
StatusUdgivet - 4 nov. 2004
Udgivet eksterntJa

Fingeraftryk

Dyk ned i forskningsemnerne om 'Aberrations of the Chk2 tumour suppressor in advanced urinary bladder cancer'. Sammen danner de et unikt fingeraftryk.

Citationsformater