The human protein kinase HIPK2 phosphorylates and downregulates the methyl-binding transcription factor ZBTB4
- 18 May 2009
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 28 (27), 2535-2544
- https://doi.org/10.1038/onc.2009.109
Abstract
HIPK2 is a eukaryotic Serine–Threonine kinase that controls cellular proliferation and survival in response to exogenous signals. Here, we show that the human transcription factor ZBTB4 is a new target of HIPK2. The two proteins interact in vitro, colocalize and associate in vivo, and HIPK2 phosphorylates several conserved residues of ZBTB4. Overexpressing HIPK2 causes the degradation of ZBTB4, whereas overexpressing a kinase-deficient mutant of HIPK2 has no effect. The chemical activation of HIPK2 also decreases the amount of ZBTB4 in cells. Conversely, the inhibition of HIPK2 by drugs or by RNA interference causes a large increase in ZBTB4 levels. This negative regulation of ZBTB4 by HIPK2 occurs under normal conditions of cell growth. In addition, the degradation is increased by DNA damage. These findings have two consequences. First, we have recently shown that ZBTB4 inhibits the transcription of p21. Therefore, the activation of p21 by HIPK2 is two-pronged: stimulation of the activator p53, and simultaneous repression of the inhibitor ZBTB4. Second, ZBTB4 is also known to bind methylated DNA and repress methylated sequences. Consequently, our findings raise the possibility that HIPK2 might influence the epigenetic regulation of gene expression at loci that remain to be identified.Keywords
This publication has 74 references indexed in Scilit:
- Zbtb4 represses transcription of P21CIP1 and controls the cellular response to p53 activationThe EMBO Journal, 2008
- Methyl-CpG binding proteins: specialized transcriptional repressors or structural components of chromatin?Cellular and Molecular Life Sciences, 2008
- Homeodomain-Interacting Protein Kinase-2 (HIPK2) Phosphorylates HMGA1a at Ser-35, Thr-52, and Thr-77 and Modulates Its DNA Binding AffinityJournal of Proteome Research, 2007
- Quantitative genetic correlation between trait and preference supports a sexually selected sperm processProceedings of the National Academy of Sciences of the United States of America, 2007
- HIPK2 represses β-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesisProceedings of the National Academy of Sciences, 2007
- Postcopulatory Sexual Selection Is Associated with Reduced Variation in Sperm MorphologyPLOS ONE, 2007
- High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2JCI Insight, 2007
- Autoregulatory control of the p53 response by caspase-mediated processing of HIPK2The EMBO Journal, 2006
- Sperm design and sperm functionBiology Letters, 2006
- A Family of Human Zinc Finger Proteins That Bind Methylated DNA and Repress TranscriptionMolecular and Cellular Biology, 2006