HGNC Approved Gene Symbol: HIPK2
Cytogenetic location: 7q34 Genomic coordinates (GRCh38) : 7:139,561,570-139,777,998 (from NCBI)
HIPK2 is a conserved serine/threonine nuclear kinase that interacts with homeodomain transcription factors.
By database searching and PCR of a brain cDNA library, Hofmann et al. (2000) obtained a cDNA encoding HIPK2. The deduced 1,191-amino acid protein contains a conserved N-terminal kinase domain with a DYRK (see DYRK1B; 604556) motif, a nuclear localization sequence, and a PEST domain. The authors showed that the kinase activity of HIPK2 is dependent on the presence of a lysine reside at position 221.
Using a yeast 2-hybrid screen of a liver cDNA library with the cytoplasmic region of CD95 (TNFRSF6; 134637) as bait, followed by 5-prime RACE on a testis cDNA library, Wang et al. (2001) isolated cDNAs encoding FADD (602457) and HIPK2. The predicted 1,198-amino acid HIPK2 protein is 96% identical to the mouse protein and has a CD95-binding site between residues 754 and 899. Northern and dot blot analyses revealed weak but ubiquitous expression of an 11.0-kb transcript that was strongest in neuronal tissue. A 7.8-kb transcript was also detected in uterus, and a strong 1.4-kb transcript was found in pancreas. Confocal microscopy demonstrated a nuclear dot localization even with a C-terminal deletion or a kinase-defective mutant. HIPK2 expressed in cells did not directly associate with CD95 or TNFR1 (191190), but did associate with TRADD (603500).
Pierantoni et al. (2002) showed that Hipk2 mRNA expression is detectable in day-15 mouse embryos and is strong in day-17 mouse embryos. In situ hybridization analysis demonstrated expression in neural retina, telencephalon, and muscle at day 16.5. RT-PCR analysis detected ubiquitous but variable expression in adult mice. Expression in humans was lower, with relatively strong expression restricted to heart, muscle, and kidney. Expression was downregulated in most human breast and thyroid carcinomas tested. Pierantoni et al. (2002) proposed that this downregulation and the loss of heterozygosity observed at chromosome 7q32-q33 in some neoplasms suggest that HIPK2 is a candidate tumor suppressor gene.
Hofmann et al. (2002) demonstrated that HIPK2 colocalizes and interacts with p53 (191170) and CREB-binding protein (CBP; 600140) within promyelocytic leukemia nuclear bodies. Activation of HIPK2 by ultraviolet (UV) radiation led to the selective phosphorylation of p53 at ser46, facilitating CBP-mediated acetylation of p53 at lys382 and promoting p53-dependent gene expression. Hofmann et al. (2002) concluded that the HIPK2 kinase function enhances expression of p53 target genes, resulting in growth arrest and the enhancement of UV-induced apoptosis. UV-induced apoptosis could be inhibited by antisense to HIPK2.
Independently, D'Orazi et al. (2002) also showed that HIPK2 phosphorylates p53 at ser46. They observed colocalization of HIPK2 with p53 and PML3, an isoform of PML (102578), in nuclear bodies and activation of HIPK2 after exposure to UV.
By yeast 3-hybrid analysis, Zhang et al. (2003) found that mouse Hipk2 interacted with an E1A-Ctbp (CTBP1; 602618) complex. Expression of Hipk2 or exposure to UV irradiation reduced Ctbp levels via a proteasome-mediated pathway. Coexpression of kinase-inactive Hipk2 or small interfering RNA-mediated reduction in Hipk2 levels prevented the UV effect. Mutation of Ctbp ser422 prevented phosphorylation as well as UV- and Hipk2-directed Ctbp clearance. Deletion of Ctbp or reduction in Ctbp levels promoted apoptosis in p53-deficient cells.
Rinaldo et al. (2007) stated that phosphorylation of p53 on ser46 shifts the affinity of p53 for promoters of genes involved in cell cycle arrest to promoters of genes involved in apoptosis. They observed that lethal DNA damage increased HIPK2 expression, whereas sublethal DNA damage repressed HIPK2 expression. Rinaldo et al. (2007) identified HIPK2 as a target for MDM2 (164785)-mediated ubiquitin-dependent degradation and found that HIPK2 degradation only occurred in growth-arresting conditions when MDM2 was efficiently induced by p53.
In human colon cancer cells, Nardinocchi et al. (2007) found that knockdown of HIPK2 using small interfering RNA reduced p53 binding and activation of p53R2 (RRM2B; 604712), resulting in impaired UV-induced DNA repair. Exogenous overexpression of p53 was able to overcome this defect.
Zhang et al. (2005) determined that the HIPK2 gene contains 13 exons and spans more than 59 kb.
Hofmann et al. (2000) mapped the HIPK2 gene to chromosome 7q32-q34 by FISH. They mapped the mouse gene to chromosome 6B. Wang et al. (2001) mapped the HIPK2 gene to chromosome 7q33-q35 by FISH.
Somatic Mutations
Li et al. (2007) identified 2 apparently somatic mutations in the HIPK2 gene, R868W and N958I, in 1 of 80 cases of myelodysplastic syndrome (MDS) and 1 of 50 cases of acute myeloid leukemia (AML; 601626), respectively. Both mutations occurred in the speckle-retention signal domain of HIPK2. Subcellular localization studies showed that the 2 mutants were localized to nuclear regions with conical or ring shapes and were somewhat diffused in the nucleus, compared to the wildtype proteins, which were mainly localized in nuclear speckles. Mutant proteins showed decreased activity and a dominant-negative effect over the wildtype protein in AML1- (151385) and p53-dependent transcription. The findings suggested that dysfunction of HIPK2 may play a role in the pathogenesis of leukemia.
Yu et al. (2009) found that 42 (60%) of 70 sporadic pilocytic astrocytomas (see 137800) had rearrangements of the BRAF gene (164757) on chromosome 7q34. Twenty-two of 36 tumors with BRAF rearrangements had corresponding amplification of the neighboring HIPK2 gene. However, 14 of 36 tumors with BRAF rearrangement had no detectable HIPK2 gene amplification. Six of 20 tumors demonstrated HIPK2 amplification without apparent BRAF rearrangement or mutation. Only 12 (17%) of the 70 tumors lacked detectable BRAF or HIPK2 alterations. Yu et al. (2009) concluded that BRAF rearrangement represents the most common genetic alteration in sporadic pilocytic astrocytomas, but suggested that HIPK2 changes may represent another contributor to the disease.
D'Orazi, G., Cecchinelli, B., Bruno, T., Manni, I., Higashimoto, Y., Saito, S., Gostissa, M., Coen, S., Marchetti, A., Del Sal, G., Piaggio, G., Fanciulli, M., Appella, E., Soddu, S. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis. Nature Cell Biol. 4: 11-19, 2002. [PubMed: 11780126] [Full Text: https://doi.org/10.1038/ncb714]
Hofmann, T. G., Mincheva, A., Lichter, P., Droge, W., Schmitz, M. L. Human homeodomain-interacting protein kinase-2 (HIPK2) is a member of the DYRK family of protein kinases and maps to chromosome 7q32-q34. Biochimie 82: 1123-1127, 2000. [PubMed: 11120354] [Full Text: https://doi.org/10.1016/s0300-9084(00)01196-2]
Hofmann, T. G., Moller, A., Sirma, H., Zentgraf, H., Taya, Y., Droge, W., Will, H., Schmitz, M. L. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nature Cell Biol. 4: 1-10, 2002. [PubMed: 11740489] [Full Text: https://doi.org/10.1038/ncb715]
Li, X.-L., Arai, Y., Harada, H., Shima, Y., Yoshida, H., Rokudai, S., Aikawa, Y., Kimura, A., Kitabayashi, I. Mutations of the HIPK2 gene in acute myeloid leukemia and myelodysplastic syndrome impair AML1- and p53-mediated transcription. Oncogene 26: 7231-7239, 2007. [PubMed: 17533375] [Full Text: https://doi.org/10.1038/sj.onc.1210523]
Nardinocchi, L., Puca, R., Sacchi, A., D'Orazi, G. HIPK2 knock-down compromises tumor cell efficiency to repair damaged DNA. Biochem. Biophys. Res. Commun. 361: 249-255, 2007. [PubMed: 17658469] [Full Text: https://doi.org/10.1016/j.bbrc.2007.07.031]
Pierantoni, G. M., Bulfone, A., Pentimalli, F., Fedele, M., Iuliano, R., Santoro, M., Chiariotti, L., Ballabio, A., Fusco, A. The homeodomain-interacting protein kinase 2 gene is expressed late in embryogenesis and preferentially in retina, muscle, and neural tissues. Biochem. Biophys. Res. Commun. 290: 942-947, 2002. [PubMed: 11798164] [Full Text: https://doi.org/10.1006/bbrc.2001.6310]
Rinaldo, C., Prodosmo, A., Mancini, F., Iacovelli, S., Sacchi, A., Moretti, F., Soddu, S. MDM2-regulated degradation of HIPK2 prevents p53Ser46 phosphorylation and DNA damage-induced apoptosis. Molec. Cell 25: 739-750, 2007. [PubMed: 17349959] [Full Text: https://doi.org/10.1016/j.molcel.2007.02.008]
Wang, Y., Hofmann, T. G., Runkel, L., Haaf, T., Schaller, H., Debatin, K.-M., Hug, H. Isolation and characterization of cDNAs for the protein kinase HIPK2. Biochim. Biophys. Acta 1518: 168-172, 2001. [PubMed: 11267674] [Full Text: https://doi.org/10.1016/s0167-4781(00)00308-0]
Yu, J., Deshmukh, H., Gutmann, R. J., Emnett, R. J., Rodriguez, F. J., Watson, M. A., Nagarajan, R., Gutmann, D. H. Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 73: 1526-1531, 2009. [PubMed: 19794125] [Full Text: https://doi.org/10.1212/WNL.0b013e3181c0664a]
Zhang, D., Li, K., Erickson-Miller, C. L., Weiss, M., Wojchowski, D. M. DYRK gene structure and erythroid-restricted features of DYRK3 gene expression. Genomics 85: 117-130, 2005. [PubMed: 15607427] [Full Text: https://doi.org/10.1016/j.ygeno.2004.08.021]
Zhang, Q., Yoshimatsu, Y., Hildebrand, J., Frisch, S. M., Goodman, R. H. Homeodomain interacting protein kinase 2 promotes apoptosis by downregulating the transcriptional corepressor CtBP. Cell 115: 177-186, 2003. [PubMed: 14567915] [Full Text: https://doi.org/10.1016/s0092-8674(03)00802-x]