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c-abl is involved in the association of p53 and trk A
A Brown1, C Browes, M Mitchell
1Cancer Research Unit, Medical School, Framlington Place, University of Newcastle, Newcastle Upon Tyne NE2 4HH, UK.
Abstract:
The p53 tumour suppressor phosphoprotein associates with proteins involved in DNA replication, transcription, cell cycle machinery and regulation of its own expression. Recently it has been shown that p53 can also bind to trk A tyrosine kinase which is the receptor for nerve growth factor (NGF). This study demonstrates that p53 appears to associate with trk A via c-abl. Endogenous c-abl was detected when the trk A and p53 complex was immunoprecipitated from lysates of NGF stimulated NIH3T3 cells expressing trk A or NIH3T3 cells expressing trk A and a temperature sensitive p53 (val 135). Endogenous c-abl and trk A association was observed in NGF stimulated p53 negative fibroblasts transfected with trk A alone; suggesting that c-abl can independently bind to trk A in the absence of p53. Interestingly, association between endogenous p53 and trk A was not detected in NGF stimulated abl negative fibroblasts transfected with trk A or when these cells were exposed to gamma radiation. This result suggests that p53 preferentially binds to trk A in the presence of c-abl and that p53 and trk A do not appear to associate directly even if p53 is activated and its levels increased by gamma radiation. Overall, these data suggest that c-abl is possibly acting as an adaptor or bridge between p53 and trk A. Oncogene (2000).
Insights
The tumor suppressor p53 protein interacts with trk A, a nerve growth factor receptor, but requires the c-abl protein to bridge the association. This suggests c-abl acts as an adaptor protein linking p53 and trk A signaling pathways.
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- The p53 tumor suppressor protein regulates DNA replication, transcription, and cell cycle progression.
- p53 has been shown to interact with trk A, the receptor for nerve growth factor (NGF).
Purpose of the Study:
- To investigate the mechanism by which p53 associates with trk A.
- To determine the role of c-abl in the p53-trk A interaction.
Main Methods:
- Immunoprecipitation assays were performed on NIH3T3 cells expressing trk A and/or a temperature-sensitive p53 mutant.
- Cells were stimulated with NGF, and the presence of c-abl, trk A, and p53 complexes was analyzed.
- Experiments were also conducted in abl-negative fibroblasts to assess the necessity of c-abl.
Main Results:
- Endogenous c-abl was detected in trk A and p53 immunoprecipitates from NGF-stimulated cells.
- c-abl independently associated with trk A in the absence of p53.
- p53-trk A association was not detected in abl-negative cells, even after gamma radiation-induced p53 activation.
- These findings indicate p53 preferentially binds trk A in a c-abl-dependent manner.
Conclusions:
- The c-abl protein likely acts as an adaptor or bridge facilitating the interaction between p53 and trk A.
- The direct association between p53 and trk A is unlikely, even upon p53 activation.