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Regulation of p73 by c-Abl through the p38 MAP kinase pathway
Ricardo Sanchez-Prieto1, Victor Javier Sanchez-Arevalo, Joan-Marc Servitja
1Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4330, USA.
Abstract:
p73 is a novel member of the p53 family of tumor suppressor proteins which is involved in cellular differentiation, tumor suppression, and the response to genotoxic stress. The molecular mechanisms regulating p73 activity are still poorly understood. Recently, p73 was found to be a target of the enzymatic activity of c-Abl, a non-receptor tyrosine kinase that potently activated in response to DNA damage. Here, we present evidence that c-Abl induces the phosphorylation of p73 in threonine residues adjacent to prolines, and that the p38 MAP kinase pathway mediates this response. Furthermore, we found that activation of p38 is sufficient to enhance the stability of p73, and that the transcriptional activation of p73 by c-Abl requires the activity of p38. These findings indicate that members of the MAP kinases superfamily of signaling molecules can regulate p73, and support a role for the p38 MAP kinase in a novel biochemical pathway by which c-Abl regulates this p53-related molecule.
Insights
The p38 MAP kinase pathway regulates the tumor suppressor p73, a protein related to p53. This pathway enhances p73 stability and is crucial for c-Abl
Area of Science:
- Molecular Biology
- Cell Signaling
- Cancer Research
Background:
- p73 is a tumor suppressor protein in the p53 family, crucial for cellular differentiation and DNA damage response.
- Mechanisms controlling p73 activity remain largely unknown.
- c-Abl, a tyrosine kinase activated by DNA damage, targets p73.
Purpose of the Study:
- To elucidate the molecular mechanisms regulating p73 activity, specifically the role of c-Abl and associated signaling pathways.
- To investigate the involvement of the p38 MAP kinase pathway in c-Abl-mediated regulation of p73.
Main Methods:
- Investigated c-Abl-induced phosphorylation of p73.
- Utilized p38 MAP kinase pathway activators and inhibitors.
- Assessed p73 stability and transcriptional activity.
Main Results:
- c-Abl induces phosphorylation of p73 at specific threonine residues.
- The p38 MAP kinase pathway mediates c-Abl's effects on p73.
- p38 activation enhances p73 protein stability.
- Transcriptional activation of p73 by c-Abl is dependent on p38 activity.
Conclusions:
- The p38 MAP kinase pathway is a key regulator of p73 activity.
- c-Abl utilizes the p38 pathway to modulate p73 stability and function.
- This study reveals a novel signaling pathway involving MAP kinases in the regulation of p73.