Regulation of p73 by c-Abl through the p38 MAP kinase pathway.
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.
Sanchez-Prieto
Ricardo
R
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4330, USA.
Sanchez-Arevalo
Victor Javier
VJ
Servitja
Joan-Marc
JM
Gutkind
J Silvio
JS
D001859:Bone Neoplasms / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D016313:Genes, abl; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney; D048369:MAP Kinase Kinase 1; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000473:pathology; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D018909:src Homology Domains
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009687:Nuclear Proteins; D011725:Pyridines; D011993:Recombinant Fusion Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D010768:Phosphoserine; D019000:Phosphotyrosine; D011392:Proline; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; C482125:MAP2K1 protein, human; C482566:MAP2K6 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580