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Transactivation-deficient Delta TA-p73 inhibits p53 by direct competition for DNA binding: implications for
Thorsten Stiewe1, Carmen C Theseling, Brigitte M Pützer
1Centre for Cancer Research and Cancer Therapy, Institute of Molecular Biology, University of Essen, Medical School, D-45122 Essen, Germany.
Abstract:
The p53 family member p73 displays significant structural and functional homology to p53. However, instead of mutational inactivation, overexpression of wild-type p73 has been reported in various tumor types compared with normal tissues, arguing against a classical tumor suppressor function. Recently, N-terminally truncated, transactivation-deficient p73 isoforms (DeltaTA-p73) have been identified as a second class of p73 proteins. Because overexpression of p73 in tumors includes DeltaTA-p73, we further characterized these novel p73 isoforms. We show that DeltaTA-p73 retains DNA-binding competence but lacks transactivation functions, resulting in an inability to induce growth arrest and apoptosis. Importantly, DeltaTA-p73 acts as a dominant-negative inhibitor of p53 and full-length p73 (TA-p73). We demonstrate that inhibition of p53 involves competition for DNA binding, whereas TA-p73 can be inhibited by direct protein-protein interaction. Further, we show that up-regulation of endogenous p73 just like ectopic overexpression of DeltaTA-p73 confers resistance to p53-mediated apoptosis induced by the chemotherapeutic agent H-7. Because inhibition of p53 is a common theme in human cancer, our data strongly support a role of DeltaTA-p73 expression for tumor formation.
Insights
N-terminally truncated p73 isoforms (DeltaTA-p73) inhibit p53 and full-length p73, promoting tumor formation. These isoforms confer resistance to chemotherapy-induced apoptosis, suggesting a role in cancer development.
Area of Science:
- Molecular Biology
- Cancer Research
- Tumorigenesis
Background:
- The p53 family member p73 shares homology with p53 but is often overexpressed in tumors, challenging its role as a classical tumor suppressor.
- N-terminally truncated, transactivation-deficient p73 isoforms (DeltaTA-p73) represent a distinct class of p73 proteins.
Purpose of the Study:
- To characterize the function of DeltaTA-p73 isoforms.
- To investigate the role of DeltaTA-p73 in tumor formation and chemoresistance.
Main Methods:
- Assessed DNA-binding and transactivation capabilities of DeltaTA-p73.
- Investigated the inhibitory mechanisms of DeltaTA-p73 on p53 and full-length p73 (TA-p73).
- Evaluated the effect of DeltaTA-p73 on p53-mediated apoptosis using chemotherapeutic agents.
Main Results:
- DeltaTA-p73 retains DNA-binding but lacks transactivation, inhibiting apoptosis and growth arrest.
- DeltaTA-p73 acts as a dominant-negative inhibitor of p53 via DNA-binding competition and TA-p73 via protein-protein interaction.
- Up-regulation of DeltaTA-p73 confers resistance to p53-mediated apoptosis induced by H-7.
Conclusions:
- DeltaTA-p73 functions as a dominant-negative regulator, inhibiting both p53 and TA-p73.
- The expression of DeltaTA-p73 supports tumor formation by conferring resistance to apoptosis.
- Targeting DeltaTA-p73 may offer therapeutic strategies for cancers with p53 pathway alterations.