Targeted disruption of the murine homeodomain-interacting protein kinase-2 causes growth deficiency in vivo and cell cycle arrest in vitro.

The homeodomain-interacting protein kinase 2 (HIPK2) protein is a member of a recently identified family of nuclear protein kinases that are well conserved in various organisms. HIPK2 can bind to several homeotic factors and to a series of proteins involved in the regulation of cell survival and proliferation in response to morphogenetic and genotoxic signals. Here we report Hipk2-targeted disruption in mouse; Hipk2(-/-) mice are viable and fertile but significantly smaller than their wild-type littermates. This feature is present at birth and retained throughout the mouse adulthood. Mouse embryo fibroblasts from Hipk2(-/-) mice show a reduced proliferation rate, compared to the wild-type counterparts, with accumulation in the G0/G1 phase of the cell cycle and altered levels of the cell cycle regulators cyclin D and CDK6. Restoration of wild-type HIPK2 expression in Hipk2(-/-) cells rescues the normal phenotype supporting a role for HIPK2 in the regulation of cell proliferation.

[1]  S. Soddu,et al.  HIPK2 is involved in cell proliferation and its suppression promotes growth arrest independently of DNA damage , 2009, Cell proliferation.

[2]  S. Soddu,et al.  HIPKs: Jack of all trades in basic nuclear activities. , 2008, Biochimica et biophysica acta.

[3]  A. Balmain,et al.  HIPK2 represses β-catenin-mediated transcription, epidermal stem cell expansion, and skin tumorigenesis , 2007, Proceedings of the National Academy of Sciences.

[4]  F. Mancini,et al.  MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. , 2007, Molecular cell.

[5]  A. Fusco,et al.  High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2. , 2007, The Journal of clinical investigation.

[6]  M. Schmitz,et al.  HIPK2, a Versatile Switchboard Regulating the Transcription Machinery and Cell Death , 2007, Cell cycle.

[7]  A. Möller,et al.  Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate protein HIPK2. , 2006, Molecular cell.

[8]  A. Fusco,et al.  High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity , 2006, Cell Death and Differentiation.

[9]  G. Del Sal,et al.  Autoregulatory control of the p53 response by caspase‐mediated processing of HIPK2 , 2006, The EMBO journal.

[10]  Haruhiko Koseki,et al.  Overlapping Roles for Homeodomain-Interacting Protein Kinases Hipk1 and Hipk2 in the Mediation of Cell Growth in Response to Morphogenetic and Genotoxic Signals , 2006, Molecular and Cellular Biology.

[11]  Jiahuai Han,et al.  Axin stimulates p53 functions by activation of HIPK2 kinase through multimeric complex formation , 2004, The EMBO journal.

[12]  E. Huang,et al.  Interaction of Brn3a and HIPK2 mediates transcriptional repression of sensory neuron survival , 2004, The Journal of cell biology.

[13]  S. Ishii,et al.  Differential Sensitivity of v-Myb and c-Myb to Wnt-1-induced Protein Degradation* , 2004, Journal of Biological Chemistry.

[14]  M. Crescenzi,et al.  Wild-type p53 gene transfer is not detrimental to normal cells in vivo: implications for tumor gene therapy , 2004, Oncogene.

[15]  Qinghong Zhang,et al.  Homeodomain Interacting Protein Kinase 2 Promotes Apoptosis by Downregulating the Transcriptional Corepressor CtBP , 2003, Cell.

[16]  S. Ishii,et al.  Requirement of the Co-repressor Homeodomain-interacting Protein Kinase 2 for Ski-mediated Inhibition of Bone Morphogenetic Protein-induced Transcriptional Activation* , 2003, Journal of Biological Chemistry.

[17]  S. Um,et al.  Identification and Characterization of HIPK2 Interacting with p73 and Modulating Functions of the p53 Familyin Vivo * , 2002, The Journal of Biological Chemistry.

[18]  G. Viglietto,et al.  High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase protein which inhibits cell growth , 2001, Oncogene.

[19]  P. Lichter,et al.  Human homeodomain-interacting protein kinase-2 (HIPK2) is a member of the DYRK family of protein kinases and maps to chromosome 7q32-q34. , 2000, Biochimie.

[20]  H. Kwon,et al.  The Homeodomain Protein NK-3 Recruits Groucho and a Histone Deacetylase Complex to Repress Transcription* , 1999, The Journal of Biological Chemistry.

[21]  Yongsok Kim,et al.  Homeodomain-interacting Protein Kinases, a Novel Family of Co-repressors for Homeodomain Transcription Factors* , 1998, The Journal of Biological Chemistry.

[22]  Sheng-Cai Lin,et al.  Daxx cooperates with the Axin/HIPK2/p53 complex to induce cell death. , 2007, Cancer research.

[23]  P. Janak,et al.  Essential function of HIPK2 in TGFβ-dependent survival of midbrain dopamine neurons , 2007, Nature Neuroscience.

[24]  Yoichi Taya,et al.  Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2 , 2002, Nature Cell Biology.

[25]  Giulia Piaggio,et al.  Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis , 2002, Nature Cell Biology.

[26]  G. Nolan,et al.  Generation of retroviral vector for clinical studies using transient transfection. , 1999, Human gene therapy.