Τίτλος:
Effects of p53 mutants derived from lung carcinomas on the
p53-responsive element (p53RE) of the MDM2 gene
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
The present study represents a continuation of previous works in which
we observed that lung carcinomas co-expressing MDM2 protein and p53
mutants (mt p53) exhibited more aggressive behaviour. In the above
studies, we suggested a ‘gain of function’ mechanism of mt p53 proteins
based on the fact that the MDM2 gene possesses a p53-responsive element
(MDM2-p53RE). In this study, to prove our hypothesis, we selected 12
cases from a series of 51 bronchogenic carcinomas. In these 12 cases, we
examined the ability of the expressed mt p53 to bind the MDM2-p53RE and
correlated the findings with MDM2 expression. Furthermore, we
constructed four of these p53 mutants and studied their transactivation
properties by co-transfecting them with a reporter plasmid carrying
MDM2-p53RE in the p53 null non-small-cell lung carcinoma cell line
(NSCLC) H1299. We observed mutant p53 protein DNA-binding activity,
which depended on the nature and the position of the amino acid
substitution. The fact that the cases with DNA-binding activity were
accompanied with MDM2 protein isoforms’ overexpression is indicative of
a ‘gain of function’ phenotype. This hypothesis was enforced by the
findings of the transfection experiments, which revealed that certain
p53 mutants enhanced the expression of the luciferase reporter gene
either directly or indirectly via a dominant positive effect on the
wild-type p53. In conclusion, this work is one first attempt to examine
if the deregulation of the p53/MDM2 autoregulatory feedback loop is due
to novel properties of certain p53 mutants in the specific environment
of a subset of bronchogenic carcinomas.
Συγγραφείς:
Gorgoulis, VG
Zacharatos, PV
Manolis, E
Ikonomopoulos, JA
and Damalas, A
Lamprinopoulos, C
Rassidakis, GZ
Zoumpourlis,
V
Kotsinas, A
Rassidakis, AN
Halazonetis, TD
Kittas, C
Περιοδικό:
British Journal of Cancer
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
p53 mutations; p53-responsive element; MDM2 gene; MDM2 isoforms; lung
cancer
