Role of p73 for drug resistance
Summary:
p73 is a member of the p53 tumor suppressor family. In contrast to p53, which is commonly inactivated in cancer
patients by mutations, p73 is often overexpressed with wild-type sequence. This p73 overexpression has been shown to
correlate with increased tumor aggressiveness and therapy resistance leading to an inferior patient outcome. It is
the goal of this project to understand in molecular terms how increased expression of p73 promotes tumor progression to
a drug resistant state. While non-tumor cells predominantly express the p53-like tumor suppressive isoform of p73 (TAp73),
cancer cells up-regulate a shorter inhibitory isoform (ΔNp73) resulting in the accumulation of oncogenic TAp73/ΔNp73
complexes. In the previous funding period we have applied several genomics techniques like ChIP-sequencing, gene expression
profiling and RNAi screening to reveal functions of overexpressed p73 in cancer cells. Together our data hint at an intriguing
function of p73 in DNA replication control that could enhance tolerance to chemotherapy-induced replicative stress as a novel
mechanism of drug resistance. This project will investigate how ΔNp73 controls DNA replication and how this might be
therapeutically exploited to overcome drug resistance.
Website AG Stiewe
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KLINISCHE FORSCHERGRUPPE 210 |
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