Download Gene Section HIPK2 (homeodomain interacting protein kinase 2) in Oncology and Haematology

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Gene Section
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HIPK2 (homeodomain interacting protein kinase 2)
Dirk Sombroek, Thomas G Hofmann
Deutsches Krebsforschungszentrum (dkfz.), Cellular Senescence Unit A210, Cell and Tumor Biology
Program, Heidelberg, Germany (DS, TGH)
Published in Atlas Database: March 2010
Online updated version : http://AtlasGeneticsOncology.org/Genes/HIPK2ID40824ch7q34.html
DOI: 10.4267/2042/44916
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
HIPK2-202 [ENST00000342645]; 2757 bp linear
mRNA; 918 amino acids.
Other names: DKFZp686K02111, FLJ23711, hHIPk2,
PRO0593
HGNC (Hugo): HIPK2
Location: 7q34
Pseudogene
DNA/RNA
Description
Nothing known.
Protein
HIPK2 is a protein kinase of 1198 amino acids (131
kDa); posttranslational modifications: phosphorylation,
ubiquitination, sumoylation at K25, caspase cleavage at
D916 and D977.
Contains several motifs and domains (from N- to Cterminus): a nuclear localisation signal (NLS)1 (97157), a kinase domain (192-520), an interaction domain
for homeodomain transcription factors (583-798), a
NLS2 (780-840) and a NLS3 within a speckle-retention
signal (SRS) (860-967), a PEST sequence (839-934)
and an autoinhibitory domain (935-1050).
Description
Zhang et al. (2005) reported 13 exons that span around
60 kb; however, up to 15 exons are listed in different
databases.
Transcription
Around 15 kb mRNA (full-length); 3594 bp open
reading frame.
At least two alternative transcripts.
Entrez Nucleotide:
[NM_022740.4] Homo sapiens HIPK2, transcript
variant 1; 15245 bp linear mRNA; full-length isoform,
[NM_001113239.2] Homo sapiens HIPK2, transcript
variant 2; 15164 bp linear mRNA; this variant lacks an
internal segment in the CDS, the resulting isoform is
shorter.
UniProtHB/Swiss-Prot [Q9H2X6]:
[Q9H2X6-1] full-length isoform (1),
[Q9H2X6-2] isoform (2),
[Q9H2X6-3] isoform (3).
Ensemble Gene [ENSG00000064393]; 4 transcripts:
HIPK2-001 [ENST00000406875]; 15049 bp linear
mRNA; 1198 amino acids,
Expression
HIPK2 is ubiquitously expressed (high mRNA levels in
neuronal tissues, heart, muscle and kidney); but barely
detectable at protein levels in unstressed cells. Protein
levels increase upon genotoxic stress.
Localisation
Mainly nuclear localisation, in nuclear bodies; but also
found in nucleoplasm and cytoplasm.
Function
HIPK2 is a potential tumour suppressor; in vivo data
suggest at least a role as an haploinsufficient tumour
suppressor in the skin of mice.
HIPK2 is a protein kinase that interacts with numerous
transcription factors (such as p53, AML1(RUNX1),
PAX6, c-MYB or NK3) as well as transcriptional
HIPK2-002 [ENST00000428878]; 3969 bp linear
mRNA; 1171 amino acids,
HIPK2-201 [ENST00000263551]; 14953 bp linear
mRNA; 1198 amino acids,
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
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HIPK2 (homeodomain interacting protein kinase 2)
Sombroek D, Hofmann TG
regulators (such as CBP, p300, Groucho, CtBP,
HMGA1 or Smads). In this way HIPK2 can activate or
repress
transcription
and
thereby
influence
differentiation, development and the DNA damage
response.
HIPK2 is an unstable protein in unstressed cells. It is
constantly degraded via the ubiquitin-proteasome
system (mediated by the E3 ubiquitin ligases
SIAH1/SIAH2, WSB1 and MDM2). Various types of
DNA damage (e.g. UV, IR or chemotherapeutics) lead
to stabilisation of the kinase and an HIPK2-mediated
induction of apoptosis or presumably also senescence.
HIPK2 can promote the apoptotic program via p53dependent and -independent pathways through
phosphorylation of p53 at Ser46 or phosphorylation of
the anti-apoptotic co-repressor CtBP at Ser422 (both
actions leading to the transcription of pro-apoptotic
target genes).
HIPK2 plays a role in the transcriptional regulation at
low oxigen concentrations (hypoxia).
Interestingly, HIPK2 also seems to have pro-survival
functions, at least in dopamine neurons.
Epithelial tumours (with altered beta4
integrin expression)
Oncogenesis
HIPK2 was reported to repress beta4 integrin
expression and thereby beta4-mediated tumour
progression in a p53-dependent manner. Beta4
overexpression correlates in vivo with a cytoplasmic
relocalisation of HIPK2, at least in breast cancer:
HIPK2 showed a cytoplasmic pattern in 62.5% of the
beta4-positive tumours (Bon et al., 2009).
Juvenile pilocytic astrocytomas (JPA)
Note
Benign childhood brain tumors.
Disease
A frequent amplification of HIPK2 along with BRAF
rearrangements in JPA (35 out of 53 cases) through
7q34 duplication was reported. This duplication was
more specific for JPA that originated from the
cerebellum or the optic chiasm. It was absent in other
brain tumours. If (and how) HIPK2 contributes to JPA
development is currently unclear (Jacob et al., 2009).
Homology
Cervical cancer
HIPK2 is conserved from flies to man.
Note
Surprisingly, a significant overexpression of HIPK2 in
cervical cancer was reported. But if (and how) HIPK2
contributes to the development of cervical carcinomas
remains unclear. No correlation between HIPK2
expression and grade or prognosis of the disease could
be demonstrated so far (Al-Beiti et al., 2008).
Mutations
Somatic
HIPK2 is rarely mutated (2 out of 130 cases) in acute
myeloid leukemia (AML) and myelodyplastic
syndrome (MDS) patients. Two missense mutations
(R868W and N958I) within the speckle-retention signal
(SRS) were reported. These mutations led to a changed
nuclear localisation of HIPK2 and a decreased
transactivation potential in AML1- and p53-dependent
transcription. The mutants showed dominant-negative
effects (Li et al., 2007).
AML(RUNX1)-associated leukemias
Oncogenesis
HIPK2 is inactivated on protein level by relocalisation
through a PEBP2-beta-SMMHC fusion protein.
Targeting of HIPK2 to cytoplasmic filaments and
thereby prevention of AML1(RUNX1) activation was
reported. Specifically, phosphorylation of RUNX1 and
its cofactor p300 seems to be inhibited by HIPK2
relocalisation (Wee et al., 2008).
Implicated in
Thyroid and breast cancer
Oncogenesis
HIPK2 is frequently inactivated by transcriptional
downregulation in thyroid carcinomas (8 out of 14
cases) and breast carcinomas (8 out of 20 cases)
(Pierantoni et al., 2002).
References
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NK-3 recruits Groucho and a histone deacetylase complex to
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Oncogenesis
HIPK2 is inactivated on protein level by cytoplasmic
relocalisation through HMGA1. Overexpression of
HMGA1 was reported to inhibit p53-mediated
apoptosis by removing HIPK2 from the nucleus and
retaining it in the cytoplasm. Observations could be
correlated with in vivo data, at least in breast cancer.
WT p53-expressing breast carcinomas showed a low
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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
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Atlas Genet Cytogenet Oncol Haematol. 2010; 14(12)
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This article should be referenced as such:
Sombroek D, Hofmann TG. HIPK2 (homeodomain interacting
protein kinase 2). Atlas Genet Cytogenet Oncol Haematol.
2010; 14(12):1141-1144.
1144