Novel homeodomain‐interacting protein kinase family member, HIPK4, phosphorylates human p53 at serine 9

Abstract

We describe here the cloning and characterization of a novel mouse homeodomain-interacting protein kinase (HIPK)-like gene, Hipk4. Hipk4 is expressed in lung and in white adipose tissue and encodes a 616 amino acid protein that includes a serine/threonine kinase domain. We demonstrate that HIPK4 could phosphorylate human p53 protein at serine 9, both in vitro and in vivo. Among known p53-responsive promoters, activity of the human survivin promoter, which is repressed by p53, was decreased by HIPK4 in p53 functional A549 cells. Human BCL2-associated X protein-promoter activity was not affected. These findings suggest that phosphorylation of p53 at serine 9 is important for p53 mediated transcriptional repression.

HIPK1 drives p53 activation to limit colorectal cancer cell growth

“…Unlike the rest of the cohort, most of them (70%) harbored a native p53 protein, indicating that other members of the family: HIPK2 24 and the more recently described HIPK4. 25 HIPK4 is structurally distant from HIPK1 and localizes exclusively in the cytosol. It has been shown to phosphorylate p53 on its serine 9, enhancing its repressor function on the survivin promoter.…”

“…It has been shown to phosphorylate p53 on its serine 9, enhancing its repressor function on the survivin promoter. 25 HIPK2, which is probably the best-characterized isoform of the family, shares a high percentage of homology with HIPK1. It also acts on p53 by triggering serine 46 phosphorylation upon DNA damage response (DDR) to allow the activation of the p53-dependent apoptotic program.…”

Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia

“…30,31 The HIPKs were originally identified as nuclear protein kinases that function as corepressors for various HD-containing transcription factors but were also recently shown to interact with other proteins involved in apoptosis and signal transduction in a cellular localization-dependent manner. HIPK1 physically interacts with and promotes phosphorylation of, for example, TP53, DAXX, EP300 and RUNX1.…”

Arsenic-Induced Activation of the Homeodomain-Interacting Protein Kinase 2 (HIPK2) to cAMP-Response Element Binding Protein (CREB) Axis

“…In addition to these nuclear HIPK1-3, HIPK4 is a cytoplasmic and much smaller HIPK family member containing a different kinase domain from HIPK1-3[32]. Among the HIPK family members, HIPK2 has been most studied and characterized as a DNA-damage responsive kinase serving as both pro-apoptotic and anti-apoptotic functions in response to genotoxic and oxidative cell damage [33–37].…”