Disease relevance of HIPK2

• HIPK2 regulates transforming growth factor-beta-induced c-Jun NH(2)-terminal kinase activation and apoptosis in human hepatoma cells [1].
• US11 of herpes simplex virus type 1 interacts with HIPK2 and antagonizes HIPK2-induced cell growth arrest [2].
• We have also found that HIPK2 expression is reduced in breast and thyroid carcinomas, suggesting a role of this gene in the process of carcinogenesis [3].
• We compared the gene expression of HIPK2 and cPLA2 in human colorectal cancer specimens by reverse transcriptase-PCR [4].
• HIPK2 mRNA levels were significantly higher in colorectal cancers of patients with familial adenomatous polyposis, which showed undetectable cPLA2 levels compared with sporadic colorectal cancer expressing cPLA2 [4].

High impact information on HIPK2

• Inducible phosphorylation of Pc2 at threonine 495 is required for its ability to increase HIPK2 sumoylation in response to DNA damage, thereby establishing an autoregulatory feedback loop between a SUMO substrate and its cognate E3 ligase [5].
• DNA damage-induced HIPK2 directly phosphorylates Pc2 at multiple sites, which in turn controls Pc2 sumoylation and intranuclear localization [5].
• The serine/threonine kinase HIPK2 phosphorylates the p53 protein at Ser 46, thus promoting p53-dependent gene expression and subsequent apoptosis [6].
• The active HIPK2 fragments are further degraded during the execution and termination phase of apoptosis, thus ensuring the occurrence of HIPK2 signaling only during the early phases of apoptosis induction [6].
• The resulting C-terminally truncated HIPK2 forms show an enhanced induction of the p53 response and cell death, thus allowing the rapid amplification of the p53-dependent apoptotic program during the initiation phase of apoptosis by a regulatory feed-forward loop [6].

Chemical compound and disease context of HIPK2

• EXPERIMENTAL DESIGN: In the human colorectal cancer cell line, RKO, we studied the effect of RNA interference for HIPK2 (HIPK2i) on prostanoid biosynthesis, both in the absence and in the presence of the cPLA2 inhibitor arachidonyl trifluoromethyl ketone [4].

Biological context of HIPK2

• Finally, we demonstrate that knockdown of endogenous HIPK2 using RNA interference inhibits TGF-beta-induced JNK activation and apoptosis [1].
• A dominant negative form of HIPK2, in which the ATP binding motif in the kinase domain and the putative phosphorylation sites were mutated, enhanced Smad1/4-dependent transcription and the BMP-induced expression of alkaline phosphatase [7].
• These results indicate that HIPK2, together with c-Ski, plays an important role in the negative regulation of BMP-induced transcriptional activation [7].
• HIPK2 shows overlapping localization with p53 in promyelocytic leukemia (PML) nuclear bodies (PML-NBs) and functionally interacts with p53 to increase gene expression [8].
• Downregulation of Sp100 levels by expression of siRNA does not interfere with p53-mediated transcription, but obviates the enhancing effect of HIPK2 [8].

Anatomical context of HIPK2

• We have recently demonstrated that the HIPK2 protein interacts with HMGA1 proteins in vitro and in vivo and that HIPK2 exerts a potent inhibitory effect on the cell growth of different normal cell lines [3].
• Furthermore, the knock-down of either endogenous or exogenous HIPK2 expression with HIPK2 shRNA markedly inhibited Pax6 phosphorylation and its transactivating function on proglucagon promoter in cultured cells [9].
• HIPK2-overexpressing AGM-derived nonadherent cells did not form cobblestone-like colonies in cultures with stromal cells [10].

Associations of HIPK2 with chemical compounds

• Homeodomain-interacting protein kinase 2 (HIPK2) is a serine/threonine kinase involved in transcriptional regulation and apoptosis [1].
• Homeodomain-interacting protein kinase 2 (HIPK2) is a nuclear serine/threonine kinase of the subfamily of dual-specificity Yak1-related kinase proteins [2].
• Here we show that human HIPK2 is modified by sumoylation at lysine 25, as revealed by in vivo and in vitro experiments [11].
• Overexpression of HIPK2 leads to an increase of p53 protein expression or stability, which becomes enhanced further in the presence of the DNA damaging drug doxorubicin [12].
• Phosphorylation-Dependent Control of Pc2 SUMO E3 Ligase Activity by Its Substrate Protein HIPK2 [5].
• The ubiquitination and degradation of HIPK2 by WSB-1 was inhibited completely via the administration of DNA damage reagents, including Adriamycin and cisplatin [13].

Physical interactions of HIPK2

• The HIPK2 protein is a critical regulator of apoptosis and functionally interacts with p53 to increase gene expression [11].
• We address here the involvement of the homeodomain-interacting protein kinase 2 (HIPK2)/p53 complex on MDM2 regulation following apoptotic DNA damage [14].
• From our yeast two-hybrid screen, we found that four and a half LIM domains 2 (FHL2) could bind to the C-terminal half of HIPK2 [15].
• High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase protein which inhibits cell growth [16].
• A carboxy- and an amino-terminal deletion of HIPK2 do not seem to be able to bind to RanBPM [17].

Enzymatic interactions of HIPK2

• HIPK2 phosphorylates CtBP at Ser-422 in vitro [18].
• Recent studies have shown that, following DNA damage, the HIPK2 serine/threonine kinase binds and phosphorylates p53, inducing p53 transcriptional activity and apoptotic function [19].

Regulatory relationships of HIPK2

• First, in wtp53-carrying cells HIPK2-dependent p53Ser46 phosphorylation selectively inhibits MDM2 at transcriptional level [14].
• Here we demonstrate that HIPK2 regulates transforming growth factor (TGF) beta-induced c-Jun NH(2)-terminal kinase (JNK) activation and apoptosis [1].
• HIPK2 efficiently inhibited Smad1/4-induced transcription from the Smad site-containing promoter [7].
• Our previous studies indicate that HIPK2 participates in a pathway of UV-triggered CtBP clearance that results in cell death [18].
• RESULTS AND CONCLUSIONS: We show here that HIPK2 activates transcription mediated by tumor suppressor p53 responsive promoter elements [12].
• Concordantly, IR-induced HIPK2 accumulation is blocked by pharmacologic inhibition of ATM [20].
• Hence, cytoplasmic relocalization of HIPK2 induced by HMGA1 overexpression is a mechanism of inactivation of p53 apoptotic function that we believe to be novel [21].

Other interactions of HIPK2

• In response to DNA damage, depletion of HIPK2 by RNA-interference abolishes MDM2 protein degradation [14].
• In this study, we show that HIPK2 is a desumoylation target for the SUMO-specific protease SENP1 that shuttles between the cytoplasm and the nucleus [22].
• Although a TP53INP1s and HIPK2 additive effect was observed on apoptosis, G1 arrest was weaker when HIPK2 was transfected together with TP53INP1 [23].
• HIPK2 can be almost completely recruited to PML-NBs by the PML isoform PML IV, but not by PML-III [24].
• Taken together, our findings indicate that HIPK2 participates in the TGF-beta signaling pathway leading to JNK activation and apoptosis [1].

Analytical, diagnostic and therapeutic context of HIPK2

• We evaluated the role of HIPK2 in the cPLA2 gene regulation by reverse transcriptase-PCR, transcriptional activity, and chromatin immunoprecipitation analyses [4].
• HIPK2 gene silencing efficiently reduces the p53-mediated transcriptional activation of apoptotic gene promoters as well as apoptotic cell death after treatment with cisplatin [25].

References