Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2.
Transcriptional activity of p53, a central regulatory switch in a network controlling cell proliferation and apoptosis, is modulated by protein stability and post-translational modifications including phosphorylation and acetylation. Here we demonstrate that the human serine/threonine kinase homeodomain-interacting protein kinase-2 (HIPK2) colocalizes and interacts with p53 and CREB-binding protein (CBP) within promyelocytic leukaemia (PML) nuclear bodies. HIPK2 is activated by ultraviolet (UV) radiation and selectively phosphorylates p53 at Ser 46, thus facilitating the CBP-mediated acetylation of p53 at Lys 382, and promoting p53-dependent gene expression. Accordingly, the kinase function of HIPK2 mediates the increased expression of p53 target genes, which results in growth arrest and the enhancement of UV-induced apoptosis. Interference with HIPK2 expression by antisense oligonucleotides impairs UV-induced apoptosis. Our results imply that HIPK2 is a novel regulator of p53 effector functions involved in cell growth, proliferation and apoptosis.
Pubmed ID: 11740489 RIS Download
Animals | Apoptosis | CREB-Binding Protein | Carrier Proteins | Cell Division | Cell Nucleus | Enzyme Activation | Genes, Tumor Suppressor | Humans | Mice | Neoplasm Proteins | Nuclear Proteins | Oligonucleotides, Antisense | Protein Binding | Protein Isoforms | Protein-Serine-Threonine Kinases | Trans-Activators | Transcription Factors | Transcriptional Activation | Tumor Cells, Cultured | Tumor Suppressor Protein p53 | Tumor Suppressor Proteins | Ultraviolet Rays