Journal Article

Regulation of p73 by c-Abl through the p38 MAP kinase pathway

Sanchez-Arevalo, Victor Javier, Sanchez-Prieto, Ricardo, Gutkind, J Silvio, Servitja, Joan-Marc

2002

Overview

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.

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: Apoptosis / Biological and medical sciences / Biotechnology / Bone Neoplasms - pathology / Calcium-Calmodulin-Dependent Protein Kinases - metabolism / Cell Line / Cell physiology / DNA damage / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Enzymatic activity / Enzyme Activation / Enzyme Inhibitors - pharmacology / Epithelial Cells - metabolism / Fundamental and applied biological sciences. Psychology / Gene therapy / Genes, abl / Genes, Tumor Suppressor / Genetic aspects / Genetic regulation / Genotoxicity / Health. Pharmaceutical industry / Humans / Imidazoles - pharmacology / Industrial applications and implications. Economical aspects / JNK Mitogen-Activated Protein Kinases / Kidney / Kinases / MAP kinase / MAP Kinase Kinase 1 / MAP Kinase Kinase 6 / MAP Kinase Kinase 7 / MAP Kinase Signaling System / Mitogen-Activated Protein Kinase Kinases - metabolism / Mitogen-Activated Protein Kinases - antagonists & inhibitors / Mitogen-Activated Protein Kinases - metabolism / Mitogen-Activated Protein Kinases - physiology / Molecular and cellular biology / Molecular modelling / Multigene Family / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Osteosarcoma - pathology / p38 Mitogen-Activated Protein Kinases / p53 Protein / Phosphorylation / Phosphoserine - metabolism / Phosphotyrosine - metabolism / Physiological aspects / Proline - chemistry / Protein kinases / Protein Processing, Post-Translational - genetics / Protein Processing, Post-Translational - physiology / Protein-Serine-Threonine Kinases - metabolism / Protein-tyrosine kinase receptors / Protein-Tyrosine Kinases - metabolism / Proteins / Proto-Oncogene Proteins c-abl - physiology / Pyridines - pharmacology / Radiation / Recombinant Fusion Proteins - physiology / Signal transduction / src Homology Domains / Threonine / Transcription activation / Transcription, Genetic / Transfection / Tumor Cells, Cultured / Tumor Protein p73 / Tumor suppressor genes / Tumor Suppressor Proteins / Tumors